WO2012046253A2

WO2012046253A2 - Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms

Info

Publication number: WO2012046253A2
Application number: PCT/IN2011/000699
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Ghojala Venkat Reddy; Karamala Rama Subba Reddy
Original assignee: MSN Laboratories Pvt Ltd
Current assignee: MSN Laboratories Pvt Ltd
Priority date: 2010-10-08
Filing date: 2011-10-07
Publication date: 2012-04-12
Anticipated expiration: 2013-04-08
Also published as: WO2012046253A3

Abstract

A process for the preparation of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of Formula-1 is provided. The crystalline forms of its intermediates as well as the final compound are also provided.

Description

Process for the preparation of A^[2-(7-methoxy°l-naphthyl)ethyll acetamide and its novel crystalline forms

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 2980/CHE/2010 filed on 8^th Oct. 2010 and 2534/CHE/2011 filed on 25^th July. 2011 which are incorporated herein by reference.

Field of Invention:

The present invention relates to an improved process for the preparation of

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide, represented by the structural formula- 1. The present invention also provides novel crystalline forms of its intermediates as well as the final compounds.

Formula- 1

Background of the Invention:

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (herein after referred as agomelatine) and process for its preparation was first disclosed in US 5225442. The disclosed process involves eight steps, starting from 7-methoxy-l-tetralone. The said process involves the reaction of ethyl bromo acetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-l-naphthyl)acetonitrile, this being followed by reduction, and then condensation of the acetyl chloride. In the said process agomelatine was finally recrystallized from isopropyl ether. The obtained agomelatine having melting range 109-110°C. As the said process involves more number of steps, it makes the process more expensive and time-consuming. Hence there is a need to provide a process with less number of steps. Synthetic communication 2001, 31(4), 621-629 disclosed a process for the preparation of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile. The disclosed process involves the reaction of 7-methoxy-l-tetralone with acetonitrile in the presence of n-butyl lithium. Further, the said compound obtained was purified by chromatography techniques, which is difficult to perform on a large scale. Hence there is a need to avoid chromatographic purification.

US 5922771 disclosed a process for the preparation of 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine. The process disclosed a two step synthesis from 2- (l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile, which involves dehydration using an acid or a base catalyst, followed by reduction. As the said process is time-consuming and requires additional solvents and reagents, which results in the process to be more expensive. N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, has valuable pharmacological properties. N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, its preparation and its therapeutic use have been described in European Patent specification EP 0 447 285. Indeed it has the double feature of being, on the one hand, an agonist of melatoninergic system receptors and, on the other hand, an antagonist of the 5-HT2_c receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity.

In view of the pharmaceutical value of this compound, it has become an important to be able to obtain it with excellent purity, with well defined crystalline form, which is perfectly reproducible, which as a result exhibits valuable characteristics in terms of formulation and sufficiently stable to allow its storage for long periods without particular requirements for control of temperature, light, humidity or oxygen level.

The process for the preparation of agomelatine is also reported in JMC 1994, vol 37, 3231-3239. In the said process agomelatine was obtained as a crystalline solid from a mixture of toluene/hexane in the ratio of 2: 1 having melting range 109-110°C. The PXRD of the obtained compound is shown in figure-6. The said crystalline form herein is designated as Form-I. The crystalline forms II, III, IV, V and VI are reported in US7498465, US7635721, US7465905, US7358395, and US20090069434A1 respectively.

Henceforth, there is a need in the art to provide a cost-effective process for the preparation of pure agomelatine with high yield in shorter reaction time, which can reliably carried out in large scale.

Brief description of the Invention:

The present invention relates to an improved process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and novel crystalline forms of its intermediate compounds. Further, the present invention also provides a novel crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and the process for its preparation.

The first aspect of the present invention is to provide a process for the preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and/or its acid addition salt compound of general formula-6, comprising of:

a) Treating 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 with hydrogen gas in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides 2-(7- methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5, b) optionally, treating the compound of formula-5 with an acid provides its corresponding acid addition salt compound of general formula-6.

The second aspect of the present invention is to provide a process for the preparation of (E)-2-(7-methoxy-3,4-dihydrbnaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8 and/or its acid addition salt compound of general formula-9, comprising of:

a) Treating 2-( 1 -hydroxy-7-methoxy- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 with hydrogen gas in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides (E)-2-(7- methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8,

b) optionally, treating the compound of formula-8 with an acid provides its corresponding acid addition salt compound of general formula-9.

The third aspect of the present invention is to provide 2-(7-methoxy-3 ,4- dihydronaphthalen- l-yl)ethanamine hydrochloride salt compound of formula-6a and its crystalline form (herein designated as crystalline form-M).

The fourth aspect of the present invention is to provide (E)-2-(7-methoxy-3,4- dihydro naphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula- 9a and its crystalline form (herein designated as crystalline form-S).

The fifth aspect of the present invention is to provide a process for preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of aromatizing the N-(2-(7-methoxy-3 ,4-dihydronaphthalen- l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7-methoxy-3 ,4-dihydronaphthalen- l(2H)-ylidene)ethyl) acetamide compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

The sixth aspect of the present invention is to provide a process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7- methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it in a suitable hydrocarbon solvent or mixture of hydrocarbon and ester solvent to provide pure compound of formula-4, b) treating the compound of formula-4 with hydrogen gas in the presence of a metal catalyst, in a . suitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5, optionally converting it into its acid addition salt compound of general formula-6,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7,

d) optionally, isolating the compound obtained in step-c) from a suitable hydrocarbon or ester solvent to provide compound of formula-7 as a solid, e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a suitable solvent provides N-[2-(7-methoxy-l-naphthyl)ethyl] acetamide compound of formula- 1.

The seventh aspect of the present invention is to provide a process <£or the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7- methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it in a suitable hydrocarbon solvent or mixture of hydrocarbon and ester solvent to provide pure compound of formula-4, b) treating the compound of formula-4 with hydrogen gas in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base to provide (E)-2-(7-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8, optionally converting it into its acid addition salt compound of general formula-9,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula- 10,

d) optionally, isolating the compound obtained in step-c) from a suitable hydrocarbon or ether solvent to provide compound of formula- 10 as a solid, e) aromatizing the compound of .formula- 10 with a suitable aromatizing agent in a suitable solvent provides N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

The eighth aspect of the present invention is to provide a process for the purification of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4.

The ninth aspect of the present invention is to provide N-(2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid and its process for preparation.

The tenth aspect of the present invention is to provide (E)-N-(2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10 as a solid and its process for preparation.

The eleventh aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 through 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine compound of formula-5 starting from 2-(l -hydroxy-7-methoxy- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4.

The twelfth aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 through (E)-2-(7-methoxy-3,4-dihydronaphthalen- l(2H)-ylidene)ethanamine compound of formula-8 starting from 2-(l-hydroxy-7-methoxy- 1,2,3, 4-tetrahydronaphthalen-l- yl)acetonitrile compound of formula-4.

The thirteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide using a suitable solvent and aqueous base.

The fourteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide by converting it into its acid addition salt compound of general formula-2.

The fifteenth aspect of the present invention is to provide a novel crystalline form of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 (herein after designated as Form-M).

The sixteenth aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Advantages of the present Invention:

* Provides highly pure N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide with high yield.

* Avoids the usage of chromatographic purification.

* Provides N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 from 7-methoxy-l-tetralone compound of formula-3 in less number of steps, which in-turn makes the process time-saving, cost-effective and eco-friendly. « Provides the 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and/or (E)-2-(7-methoxy-3,4-dihydronaphthalen- 1 (2H)-ylidene) ethanamine compound of formula-8 from 2-( 1 -hydroxy- 7-methoxy- 1,2,3, 4- tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4 in a single step, which makes the process time-saving and cost-effective.

Brief description of drawings:

Figure-1: Illustrated the DSC thermogram of crystalline form-M of 2-(7-methoxy-3,4- dihydro naphthalen-l-yl) ethanamine hydrochloride salt compound of formula-6a.

Figure-2: Illustrated the DSC thermogram of crystalline form-S of (E)-2-(7-methoxy- 3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula-9a.

Figure-3: Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide oxalate compound of formula-2a.

Figure-4: Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide hydrochloride compound of formula-2b.

Figure-5: Illustrates the PXRD of crystalline form-M of N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide compound of formula- 1.

Figure-6: Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl)ethyl] acetamide compound of formula- 1 obtained as per the process disclosed in JMC 1994, vol 37, 3231-3239.

Detailed Description of the Invention

The present invention relates to an improved process for the preparation of pure N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 and novel crystalline forms of its intermediate as well as the final compounds.

As used herein the present invention, the term "suitable solvents" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane, pet.ether and cyclohexane; "polar aprotic solvents" like dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyethyl ketone, methyl isobutyl ketone; "alcohol solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycol and isobutanol; "chloro solvents" like dichloromethane, chloroform, and dichloroethane; and "polar solvents" like water; and also mixtures thereof.

The term "base" herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases like ammonia, triethylamine, tributyl amine, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N- methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethylamine, cyclohexyldimethyl amine, piperidine, dimethyl amino pyridine, pyridine, lithium hexamethyldisilazidem (LiHMDS), sodium hexamethyldisilazide (NaHMDS) and tetraalkyl ammonium hydroxide such as tetrabutyl ammonium hydroxide.

The term "acid" herein the present invention is selected from inorganic acids like hydrochloric acid and hydrobromic acid; and organic acid like acetic acid, oxalic acid.

The term "aromatization process" as used herein the present invention refers to a dehydrogenating process for converting alicyclic compounds into aromatic compounds. The said process can be carried out using a suitable aromatizing agent is selected from a group consisting of but not limited to, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) or a proton acceptor selected from nitro alkanes or nitro arenes such as nitromethane, nitro ethane, nitro benzene and the like, optionally in the presence of a base selected from alkali metal or alkaline earth metal or tetraalkyl ammonium hydroxides, alkoxides, carbonates and bicarbonates; and a phase transfer catalyst.

As used herein the present invention, the term "phase transfer catalyst" such as alkyl ammonium and alkyl phosphonium salts, especially bromide or other halides. Wherein, the alkyl group is straight chain or branched containing 1-20 carbon atoms, most commonly 1-12 carbon atoms such as tetramethyl, tetraethyl, tetrabutyl, tetrapentyl, methyl-trialkyl, butyltripropyl, heptyltriethyl, octyltriethyl and the like.

a) Treating the 2 -( 1 -hydroxy-7-methoxy- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl) acetonitrile compound of formula-4

Formula-4

with hydrogen gas in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4- dihydronaphthalen-l-yl) ethanamine compound of formula-5,

Formula-5

b) optionally, treating the compound of formula-5 with an acid provides its corresponding acid addition salt compound of general formula-6.

Formula-6

wherein, in step-a) the metal catalyst is Raney-Ni or Pd-C; and the step a) of the above process is carried out at a temperature of above 40°C, preferably at 45- 70°C, more preferably at 45-60°C.

In a preferred embodiment of the present invention is to provide a process for the preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and its hydrochloride salt compound of formula-6a_s comprising of:

Formula-6a

a) Treating 2-( 1 -hydroxy-7-methoxy- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 with hydrogen gas in the presence of Raney-Ni, in aqueous methanol in presence of ammonia at 45-60°C provides 2-(7-methoxy- 3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) treating the compound of formula-5 with hydrochloric acid in ethylacetate provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a.

Prior-art processes disclosed a two step process for the preparation of 2-(7- methoxy-3,4-dihydro naphthalen-l-yl)ethanamine compound of formula-5. Whereas the present invention provides a process for preparation of compound of formula-5 in a single step, which makes the process more cost-effective and time-saving. Moreover, the purity of compound of formula-5 is enhanced by converting it into its hydrochloride salt compound of formula-6a, which is useful in the synthesis of highly pure N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1. Hence the present invention is more advantageous over the prior art process.

The second aspect of the present invention is to provide a process for the preparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8 and/or its acid addition salt compound of general formula-9, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl) acetonitrile compound of formula-4 with hydrogen gas in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides (E)-2-(7-methoxy-3,4-dihydro naphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8,

Formula-8

b) optionally, treating the compound of formula-8 with an acid to provide its corresponding acid addition salt compound of general formula-9.

Formula-9

Wherein, in step-a) the metal catalyst is Raney-Ni or Pd-C; and the step-a) of the above process is carried out at a temperature below 40°C, preferably at 25-40°C, more preferably at 25-35°C.

In a preferred embodiment of the present invention is to provide a process for the preparation of (E)-2-(7-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8 and its hydrochloride salt compound of formula-9a,

comprising of:

Formula-9a

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl) acetonitrile compound of formula-4 with hydrogen gas in the presence of Raney- Ni and ammonia in aqueous methanol at 25-35°C provides (E)-2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8, b) treating the compound of formula-8 with hydrochloric acid in ethyl acetate to provide (E)-2-(7-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine hydrochloride salt compound of formula-9a.

Prior-art processes disclosed a two-step process for the preparation of (E)-2-(7- methoxy-3 ,4-dihydronaphthalen- l(2H)-ylidene)ethanamine compound of formula-8. Whereas, the present invention provides the process for preparation of compound of formula-8 in a single step, which makes the process more cost-effective and time-saving. Moreover, the purity of compound of formula-8 is enhanced by converting it into its hydrochloride salt compound of formula-9a, which is useful in the synthesis of highly pure N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1. Hence the present invention is more advantageous over the prior art process.

The third aspect of the present invention is to provide 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a. Further, the present invention also provides the crystalline form of 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a (herein designated as crystalline form-M). The crystalline form-M of compound of formula-6a is characterized by its DSC thermogram showing endotherm peak at 151.12°C substantially as shown in figure- 1.

The fourth aspect of the present invention is to provide (E)-2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula- 9a. Further, the present invention also provides the crystalline form of (E)-2-(7-methoxy- 3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula-9a (herein designated as crystalline form-S). The crystalline form-S of compound of formula-9a is characterized by its DSC thermogram showing endotherm peak at 136.87°C substantially as shown in figure-2.

The fifth aspect of the present invention is to provide a process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of aromatizing the N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Prior-art processes disclosed a process for preparation of N-(2-(7-methoxy-3,4- dihydro naphthalen-l-yl)ethyl)acetamide compound of formula-7 and (E)-N-(2-(7- methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10. Further, its conversion into N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide was not reported in the said prior-art. _{v v}

The compounds of formula-7 and formula- 10 are important intermediates in the synthesis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and these have been aromatized using a suitable aromatizing agent like DDQ to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1.

A preferred embodiment of the present invention provides N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1, which comprises of aromatizing N-(2- (7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 or (E)- N-(2-(7-methoxy-3,4-dihydro naphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10 with DDQ in dichloromethane to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1.

a) Reacting the 7-methoxy-l-tetralone compound of formula-3

Formula-3

with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4, optionally purifying it in a suitable hydrocarbon or mixture of hydrocarbon and ester solvent to provide pure compound of formula-4, b) treating the compound of formula-4 with hydrogen gas, in the presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5, optionally converting it into its acid addition salt compound of general formula-6,

Formula-7

d) optionally, isolating the compound obtained in step c) from a suitable

hydrocarbon or ester solvent to provide compound of formula-7 as a solid, e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Wherein,

In step a) the suitable base used is sodium hexamethyldisilazide,

in step b) the suitable reducing agent used is Raney-Ni or Pd-C; the acid used is acetic acid; the base used is ammonia; the suitable solvent is selected from alcohol solvents or water or mixture thereof,

in step c) the suitable acetylating agent is selected from acetyl halide, acetic anhydride and acetic acid; and the suitable solvent is selected from chloro solvents and hydrocarbon solvents and ester solvents,

The step b) of the above process is carried out at a temperature above 40°C, preferably at 45-70°C, more preferably at 45-60°C. In a preferred embodiment of the present invention is to provide a process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of sodium hexamethyldisilazide in tetrahydrofuran to provide 2-(l- hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4, which is further crystallized from cyclohexane to provide pure compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in the presence of Raney- Ni, in aqueous methanol in presence of ammonia at 45-60°C to provide 2-(7- methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 v v

followed by treatment with hydrochloric acid in ethylacetate to provide its corresponding hydrochloride salt compound of formula-6a,

c) acetylating the compound of formula-6a with acetyl chloride in the presence of potassium carbonate in aqueous ethyl acetate to provide N-(2-(7-methoxy-3,4- dihydronaphthakn-l-yl)ethyl)acetamide compound of formula-7,

d) isolating the compound obtained in step c) from cyclohexane to provide

compound of formula-7 as a solid,

e) aromatizing the compound of formula-7 with DDQ in dichloromethane to provide N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide compound of formula- 1.

In the present invention, during the process for the preparation of N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide, some process impurities are formed in higher concentrations, which led to the decrease in the purity of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide. The present invention provides a simple purification process which reduces the impurities to lower level, preferably non detectable level in HPLC.

The following impurities were formed in step a) which are listed below along with their RRT and Area % of crude compound and recrystallized compound. Table 1

These above said impurities are reduced to the level of non detection after recrystallization from cyclohexane and provides compound of formula-4 with purity of 99.74% by HPLC.

The following impurity was formed in step b) which is listed below along with its RRT and Area % of compound of formula-5, before and after salt formation.

Table 2

The above said impurity is reduced to the level of non detection, by converting the compound of formula-5 into its hydrochloride salt compound of formula-6a with purity of 99.36% by HPLC.

The following impurity is formed in step c) which is listed below along with its RRT and area %, before and after isolation from cyclohexane. Table 3

The above formed impurity is reduced to the level of non detection after isolating from cyclohexane and provides compound of formula-7 with purity of 97.48% by HPLC.

The possible impurities which can be formed in the synthesis of N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide are listed below al6ng with their RRT.

Table 4

The above impurities are controlled almost to the level of non detection in the present invention to provide N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide compound of formula- 1 with purity 99.86% by HPLC.

The seventh aspect of the present invention is to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of forrmila-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydrOxy-7- methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it in a suitable hydrocarbon solvent or mixture of hydrocarbon and ester solvent to provide pure compound of formula-4, b) treating the compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of a base or an acid provides (E)-2-(7-methoxy-3,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8, optionally converting it into its acid addition salt compound of general formula-9,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl) acetamide compound of formula- 10,

Formula- 10

d) optionally, isolating the compound obtained in step c) from a suitable

hydrocarbon or ether solvent to provide compound of formula- 10 as a solid, e) aromatizing the compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Wherein, the reagents and solvents used in step-(a), (b) and (c) of the above process is same as defined above;

The step b) of the present invention is carried out at a temperature below 40°C, preferably at 25-40°C, more preferably at 25-35°C.

The eighth aspect of the present invention is to provide a process for the purification of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4, comprising of:

a) Dissolving the 2-(l-hydroxy-7-methoxy-l ,2,3,4-tetrahydronaphthalen-l -yl)

acetonitrile compound of formula-4 in a suitable solvent by heating to higher temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture,

d) filtering the solid to provide pure compound of formula-4.

wherein, the suitable solvent used in step-a) is hydrocarbon solvent or mixture of hydrocarbon solvents and ester solvents in the range of 2 to 10 volumes, preferably 3 to 5 volumes to the compound of formula-4. The suitable hydrocarbon solvent is selected from hexane, heptane and cyclohexane; ester solvents are selected from ethyl acetate, methyl acetate and isopropyl acetate or mixtures thereof.

Synthetic communication, 2001, 31(4), 621-629 disclosed a process for the preparation of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 by using chromatographic technique, which is difficult to carry out on large scale. Whereas, in the present invention the said compound is purified by recrystallization from cyclohexane or mixture of cyclohexane and ester solvents, which avoids the chromatographic purification.

The ninth aspect of the present invention is to provide N-(2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid and is characterized by its DSC thermogram showing endotherm peak at 107.95°C.

In another embodiment of the present invention provides a process for preparation of solid N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7, comprising of:

a) Dissolving the N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 in hydrocarbon solvent or ester solvent by heating to higher temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture,

d) filtering the reaction mixture to provide compound of formula-7 as a solid.

Wherein, the solvent used in the step-a) of above aspect is in the range of 2 to 10 volumes, preferably 3 to 5 volumes to compound of formula-7.

The hydrocarbon solvent used in step-a) is selected from hexane, heptane and cyclohexane; ester solvent is selected from methyl acetate, ethyl acetate and isopropyl acetate.

The tenth aspect of the present invention is to provide (E)-N-(2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10 as a crystalline solid. In another embodiment of the present invention provides a process for preparation of solid (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen- 1 (2H)-ylidene)ethyl)acetamide compound of formula- 10, comprising of:

a) Dissolving the (E)-N-(2-(7-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethyl) acetamide compound of formula- 10 in a suitable solvent at 25-35°C,

b) stirring the reaction mixture,

c) filtering the reaction mixture to provide compound of formula- 10 as a crystalline solid.

Wherein, the solvent used in step-a) of the above aspect is in the range of 2 to 10 volumes, preferably 3 to 5 volumes to compound of formula- 10. The hydrocarbon solvent used is selected from hexane, heptane and cyclohexane; ether solvents are selected from tetrahydrofuran, diethylether, methyl tert-butyl ether and diisopropyl ether.

The eleventh aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Treating the 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)acetonitrile compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) acetylating the compound of formula-5 in-situ with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7,

c) aromatizing the compound of formula-7 in-situ with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Wherein, the step a) is carried out at a temperature above 40°C, preferably at 45- 70°C, more preferably at 45-60°C.

The twelfth aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Treating the 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)acetonitrile compound of formula-4 with hydrogen gas in presence of a metal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides (E)-2-(7-methoxy-3,4-dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8,

b) acetylating the compound of formula-8 in-situ with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l- ylidene) ethyl)acetamide compound of formula- 10,

c) aromatizing the compound of formula- 10 in-situ with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

Wherein, the step a) is carried out at a temperature below 40°C, preferably at 25- 40°C, more preferably at 25-35°C.

The thirteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Dissolving N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide compound of formula- 1 in a suitable solvent by stirring at

higher temperature,

b) cooling the reaction mixture,

c) adding aqueous base,

d) filtering the solid and washing with a aqueous base,

e) dissolving the solid obtained in step d) in a suitable solvent by heating to higher temperature,

f) treating with carbon,

g) filtering the reaction mixture and washing with a suitable solvent,

h) filtrate is added to the aqueous base and stirring the reaction mixture,

i) filtering the solid and washing with a suitable solvent to get pure N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1. Wherein, the aqueous base used in the above process is aqueous sodium hydroxide and the suitable solvent is polar aprotic solvent.

The fourteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

higher temperature,

b) adding aqueous acid solution,

c) cooling and stirring the reaction mixture,

d) filtering the solid and washing with a suitable solvent to get acid addition salt of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of general formula-2, e) adding a chloro solvent to the solid,

f) adjusting the pH of the reaction mixture to 9- 10 by adding an aqueous base, g) separating the layers and distilling off the solvent from the organic layer to get pure N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1.

Wherein, in step a) the suitable solvent is selected from ester solvent, ketone solvent, hydrocarbon solvent and polar aprotic solvent,

In step b) the acid is selected from oxalic acid, hydrochloric acid and acetic acid.

In the above aspect, N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide oxalate compound of formula-2a can also be obtained in the form of co-crystals. The PXRD of the said compound is depicted in figure-3.

The purity and description of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1 was enhanced by the above purification process disclosed in 13 and 14 aspects of the present invention.

The fifteenth aspect of the present invention is to provide a novel crystalline form of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide, which is characterized by its X-ray powder diffractogram having characteristic peaks at 11.20, 11.86, 19.55, 22.51 and 31.91 ± 0.2 degress 2Θ; hereinafter designated as form-M. The crystalline form-M of the present invention further chacterised by its PXRD peaks at 17.54, 18.38, 18.54, 19.73, 20.51, 21.78, 23.04, 24.60 and 25.39 ± 0.2 degress 2Θ. The crystalline form may also be substantially similar to the PXRD pattern depicted in Figure-5.

The sixteenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, which comprising of the following steps:

a) Dissolving the N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide compound of

formula- 1 in a suitable organic solvent selected from ketone solvents, ether solvents and alcoholic solvents, preferably ether solvents like methyl tertiary butyl ether,

b) heating the reaction mixture to 55° C to 80° C, preferably 65°C to 75°C and

stirring,

c) cooling the reaction mixture to room temperature,

d) further cooling the reaction mixture to 0-5° C and stirring,

e) filtering the precipitated solid and washing with a suitable organic solvent, f) drying the solid to get the crystalline form-M of N-[2-(7-methoxy-l- naphthyi)ethyl]acetamide.

In a preferred embodiment, the process for the preparation of novel crystalline Form-M of N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide of formula- 1 comprises of the following steps,

a) Dissolving the N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of

formula- 1 in methyl tertiary butyl ether,

b) heating the reaction mixture65-75°C and stirring for 90 min.,

c) cooling the reaction mixture to room temperature

d) further cooling the reaction mixture to 0-5° C and stirring for 2 hrs

e) filtering the precipitated solid and washing with methyl tertiary butyl ether f) drying the solid at 55-65 °C for 12-14 hrs to get crystalline form-M of

N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide.

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 obtained by the present invention is dissolved in a suitable solvent and precipitating the solid by adding water to it to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide crystalline form-I.

The suitable solvent used for the preparation of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide crystalline form-I is selected from DMF, DMSO, THF, acetonitrile, ketone solvents and alcohol solvents.

In the present invention 7-methoxy-l-tetralone compound of formula-3 can be prepared by treating the anisole with succinic anhydride in the presence of acid catalyst like aluminiumtrichloride in a suitable solvent such as chloro solvents provides 4-(4- methoxyphenyl)-4-oxobutanoic acid compound of formula-11, which is reduced with a suitable reducing agent in a suitable solvent to provide 4-(4-methoxyphenyl) butanoic acid compound of formula- 12. Cyclizing the compound of formula- 12 as per the known methods in the art (JP2004182660A) provided 7-methoxy-l-tetralone compound of formula-3.

Formula-1 1 Formula- 12 Formula-3

Wherein, the suitable reducing agent used is selected from hydrazine hydrate, triethylsilane in combination with trifluoroacetic acid and Pd-C.

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.

Compound of formula-6a and compound of formula-7 of present invention were analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column:

Intersil ODS-4, 250 x 4.6 mm, 5 μπι or equivalent; Flow rate: 1.0 ml/min; Wavelength:

220 nm; Temperature: 40°C; Injection volume: 10 μΙ_; Run time: 55 minutes; Diluent: acetonitrile: water (90: 10 v/v); Elution: Gradient; Buffer: 2.8 grams of sodium per chlorate mono hydrate into 1000 ml of water, adjust pH to 2.8 with dilute perchloric acid. Filtered this solution through 0.22 μιη Nylon membrane filter paper and sonicate to degas it; solution-A: Buffer; solution-B: acetonitrile:methanol (80:20 v/v).

Compound of formula-4 of present invention was analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Inertsil ODS-4, 250 x 4.6 mm, 5 μιη or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Temperature: 35°C; Injection volume: 10 μί; Run time: 52 minutes; Diluent: acetonitrile: water (90:10 v/v); Elution: Gradient; Buffer: 2.8 grams of sodium per chlorate mono hydrate into 1000 ml of water, adjust pH to 2.8 with dilute perchloric acid. Filtered this solution through 0.22 μτη Nylon membrane filter paper and sonicate to degas it; solution-A: Buffer; solution-B: acetonitrile:methanol (80:20 v/v).

Compound of formula- 1 of present invention was analyzed by HPJX using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Inertsil C8-3, 250 x 4.6 mm, 5 μιη or equivalent; Flow rate: 1.0 ml/min; Wavelength: 230 nm; Temperature: 45°C; injection volume : 10 μί; Run time: 52 minutes; Diluent: Acetonitrile: water (50:50 v/v); Elution: Gradient; Mobile phase-A : Buffer: acetonitrile (90: 10 v/v); Mobile phase-B: water: acetonitrile (10:90 v/v); Buffer : 2.81 grams of sodium per chlorate mono hydrate into 1000 ml of water, adjust pH to 2.2 with phosphoric acid. Filtered this solution through 0.45 μπι Nylon membrane filter paper and sonicate to degas it.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290calorimeter. Samples of about 2 to 3 milligrams washeld in a closed pan, and analyzed at a heating rate of 10° per minute.

PXRD analysis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. The present invention represented schematically as follows: Scheme 1

FormuIa-3

[Agomelatine] Formula-1

Scheme-2:

Formula-1

Formula-7 The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example- 1: Preparation of 2-(l-hydroxy-7methoxy-l,2,3,4-tetrahydronaphthalen-l- yl) acetonitrile (Formula-4)

A solution of NaHMDS (498.5 ml) in tetrahydrofuran (500 ml) was cooled to -70 to -80°C under nitrogen atmosphere. To this solution, a mixture of 7-methoxy-l-tetralone compound of formula-3 (100 g), tetrahydrofuran (200 ml) and acetonitrile (44.4 ml) was added at -70 to -80°C and then stirred for 45 minutes at the same temperature. After completion of the reaction, the reaction mixture was quenched with 10% ammonium chloride solution and extracted the product into ethylacetate. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethylacetate. Both ethyl acetate layers were combined and washed with 10% sodium chloride solution.Distilled off the solvent and co-distilled with cyclohexane to obtain title compound as a residue. Dissolving the obtained residue in cyclohexane (200 ml) by heating to 50-60°C and then cooled to 25-30°C. The reaction mixture was stirred for 1 ½ hour at 25-30°C. Filtered the obtained solid, washed with cyclohexane and then dried to get title compound. The purification using cyclohexane (1000 ml) was repeated another time to get highly pure title compound. Yield: 105 grams; MR: 83-93°C; Purity: 99.74 % by HPLC.

Example-2: Purification of 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen- 1-yl) acetonitrile (Formula-4)

Dissolving the compound of formula-4 (105 g) in a mixture of cyclohexane (263 ml) and ethyl acetate (52.5 ml) by heating to 50-60°C and then cooled to 25-30°C. The reaction mixture was stirred for 1 ½ hour at 25-30°C. Filtered the obtained solid, washed with cyclohexane and then dried to get the title compound. Yield: 95 grams; MR: 83-93°C; purity: 99.74 % by HPLC

Example-3: Preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine hydrochloride salt (Formula-6a) 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 (100 g) was added to a mixture of Raney-Ni (50 g), methanolic ammonia (600 ml) and water (25 ml) at 25-30°C in autoclave. Hydrogen gas (3-4 kg) was bubbled to the reaction mixture. The reaction mixture was heated to 45-55°C and then stirred for 6 hours at 45-50°C. After completion of the reaction, cool the autoclave to 25- 30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the filtrate obtained and cooled to 25-30°C.Co-distilled the reaction mixture twice with methanol. Ethyl acetate was added to the obtained residue at 25-30°C and then cooled to 10-15°C. The pH of the reaction mixture was adjusted to below 2.0 with ethyl acetate-hydrochloride and stirred for 2 hours at 10-15°C. The obtained solid was filtered, washed with ethyl acetate and then dried to get the title compound.

Yield: 100 grams; MP: 151.12°C; Purity: 99.36 % by HPLC.

Example-4: Preparation of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl) acetamide (Formula-7)

A mixture of 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a (100 g), ethylacetate (800 ml) and potassium carbonate (69.5 ml) was stirred for 15 minutes at 25-30°C and then cooled to 0-5°C. Acetyl chloride (29.6 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 1 hour,at 0-5°C. After completion of the reaction, the temperature of the reaction was raised to 25-30°C. Water was added to the reaction mixture and stirred for 15 minutes at same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Both the ethylacetate layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. The reaction mixture was cooled to 25-30°C to get title compound as a residue. Cyclohexane (300 ml) was added to the obtained residue and then heated to 45-50°C. The reaction mixture was stirred for 45 minutes at 45-50°C and further stirred for 1 ½ hour at 25-30°C. Filtered the obtained solid, washed with cyclohexane and then dried to get pure title compound.

Yield: 95 grams; MR: 100-110°C; Purity: 97.48 % by HPLC.

Example-5: Process for the isolation of N-(2-(7-methoxy-3,4-dihydronaphthalen-l- yl)ethyl) acetamide (Formula-7) A mixture of 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a (100 g), ethylacetate (800 ml) and potassium carbonate (69.5 ml) was stirred for 15 minutes at 25-30°C and then cooled to 0-5°C. Acetyl chloride (29.6 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 1 hour at 0-5°C. After completion of the reaction, the temperature of the reaction was raised to 25-30°C. Water was added to the reaction mixture and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Both the ethylacetate layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. The reaction mixture was cooled to 25-30°C to get title compound as a residue. Ethyl acetate (300 ml) was added to the obtained residue and then heated to 45-50°C. The reaction mixture was stirred for 45 minutes at 45-50°C and further stirred for 1 ½ hour at 25-30°C. Filtered the obtained solid, washed with ethyl acetate and then dried to get pure title compound.

Yield: 95 grams; MR: 100-110°C; Purity: 97.95 % by HPLC.

Example-6'. Preparation of jV-l2-(7-methoxy-l-naphthyl)ethyl]acetamide(Formula-l) A solution of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 (100 g) in dichloromethane (800 ml) was cooled to 0-5°C. A solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added to the above reaction mixture at 0-5°C and then stirred for 10-20 minutes. The temperature of the reaction mixture was raised to 25-30°C and then stirred for 14 hours at same temperature. After completion of the reaction, filtered the reaction mixture and washed with dichloromethane. Filtrate was washed with 0.5% sodium hydroxide solution, followed by 1% hydrochloride solution and followed by water. Distilled off the solvent completely from the dichloromethane layer and co-distilled with acetone. The obtained residue was cooled to 25-30°C. Acetone (200 ml) was added to the obtained residue and then carbon (10 g) was added to the reaction mixture. The reaction mixture was heated to reflux temperature and stirred for 20 minutes at the same temperature. Filtered the reaction mixture and washed with acetone. Filtrate was added to 2% sodium hydroxide solution at 10-15°C and then stirred for 2 hours at 10-15°C. Filtered the obtained solid, washed with 2% sodium hydroxide solution and then washed with 0.5 % hydrochloric acid and followed by water to get title compound. Acetone (140 ) was added to the obtained solid and then heated to 45-50°C. The reaction mixture was stirred for 10 minutes at 45-50°C. Filtered the reaction mixture, washed with acetone. Filtrate was added to the water and then stirred for 2 hours at 25- 30°C. Filtered the reaction mixture, washed with water and then dried to get the pure title compound. Yield: 60 grams, MR: 97-103°C; Purity (by HPLC): 99.86 %.

Example-7: Preparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanaminehydrochloride salt (Formula-9a)

2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrilecompound of formula-4 (100 g) was added to a mixture of Raney-Ni (30 g), methanolic ammonia (600 ml) and water (25 ml) at 25-30°C in autoclave. Hydrogen gas (3-4 kg) was bubbled to the reaction mixture. The reaction mixture was heated to 25-30°C and then stirred for 5 v v

hours at same temperature. After completion of the reaction, filtered the reaction mixture at 25-30°C and washed with methanol. Distilled off the solvent completely from the filtrate obtained and co-distilled with methanol. Ethylacetate (600 ml) was added to the obtained residue at 25-30°C and then cooled to same temperature. The pH of the reaction mixture was adjusted to below 2.0 with ethylacetate-hydtochloride and stirred for 3 hours at 25-35°C. The obtained solid was filtered, washed with ethylacetate and then dried to get the title compound. Yield: 103 grams; MP: 136.87°C; Purity (by HPLC): 99.57 %. Example-8: Preparation of (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide (Formula-10)

A mixture of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanamine hydrochloride salt compound of formula-9a (100 g), toluene (1000 ml) and potassium carbonate (115.48 ml) was cooled to 0-5°C. Acetyl chloride (44.5 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 1 hour at 0- 5°C. After completion of the reaction, water was added to the reaction mixture and stirred for 15 minutes at 25-35°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. Both the toluene layers were combined and washed with 5% sodium bicarbonate solution and water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cyclohexane (300 ml) was added to the obtained residue at 25-35°C and stirring the reaction mixture for 3 hrs. Allow the reaction mixture at 25-35°C until the solid precipitates. Filter the obtained solid, washed with cyclohexane and dried to get the title compound. Yield: 95 grams. Example-9: Preparation of (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide (Formula- 10)

A mixture of (E)-2-(7-methoxy-3,4-dihydronaphthalen- l(2H)-ylidene) ethanamine hydrochloride salt compound of formula-9a (100 g), toluene (1000 ml) and potassium carbonate (115.48 ml) was cooled to 0-5°C. Acetyl chloride (44.5 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 1 hour at 0- 5°C. After completion of the reaction, water was added to the reaction mixture and stirred for 15 minutes at 25-35°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. Both the toluene layers were combined and washed with 5% sodium bicarbonate solution and water. Distilled off the solvent completely from the organic layer and co-distilled with Methyl tertiary butyl ether. Methyl tertiary butyl ether (300 ml) was added to the obtained residue at 25-35°C and stirring the reaction mixture for 3 hours. Allow the reaction mixture at 25-35°C until the solid precipitates. Filter the obtained solid, washed with Methyl tertiary butyl ether and dried to get the title compound. Yield". 86 grams.

Example- 10: Preparation of 7V-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (Formula-1)

A solution of (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl) acetamide compound of formula- 10 (100 g) in dichloromethane (800 ml) was cooled to 0-5°C. A solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added to the above reaction mixture at 0-5°C and then stirred for 10-20 minutes. The temperature of the reaction mixture was raised to 25-30°C and then stirred for 14 hours at 25-30°C. After completion of the reaction, filtered the reaction mixture and washed with dichloromethane. Filtrate was washed with 0.5% sodium hydroxide solution, followed by 1% hydrochloride solution and followed by water. Distilled off the solvent completely from the dichloromethane layer and co-distilled with acetone. The obtained residue was cooled to 25-30°C. Acetone (200 ml) was added to the obtained residue and then carbon (10 g) was added to the reaction mixture. The reaction mixture was heated to reflux temperature and stirred for 20 minutes at the same temperature. Filtered the reaction mixture and washed with acetone. Filtrate was added to 2% sodium hydroxide solution at 10-15°C and then stirred for 2 hours at 10-15°C. Filtered the obtained solid, washed with 2% sodium hydroxide and then washed with 0.5 % hydrochloric acid and followed by water to get title compound. Acetone (140 ml) was added to the obtained solid and then heated to 45-50°C. The reaction mixture was stirred for 10 minutes at 45-50°C. Filtered the reaction mixture, washed with acetone. Filtrate was added to the water and then stirred for 2 hours at 25-30°C. Filtered the obtained solid, washed with water and then dried to get the pure title compound. Yield: 55 grams, MR: 97-103°C.

Example- Π : Preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide(Formula-l)

(E)-N-(2-(7-methoxy-3 ,4-dihydronaphthalen- 1 (2H)-ylidene)ethyl)acetamide compound of formula-10 (100 g) was taken in toluene (1500 ml). A solution of DDQ (111.18 g) in toluene (500 ml) was added to the above reaction mixture and stirred for 26 hours at 25-35°C. Methanol (200 ml) and 2% NaOH (1500 ml) was added to the reaction mixture and stirred for 20 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the toluene layers were combined and washed with 2 % sodium hydroxide solution and water. Distilled off the solvent completely from the toluene layer and co-distilled with dimethyl formamide. Dimethyl formamide (200 ml) was added to the obtained compound and cooled to 10-15°C. 2% NaOH solution was added to the reaction mixture for a period of 45 minutes at 10-15°C. Filter the reaction mixture, washed with 2% NaOH solution and then dried to get the solid compound. Dissolving the obtained solid in ethyl acetate (200 ml) and methanol (10 ml) by heating to 45-50°C. Cooled the reaction mixture to 0-5°C and stirred for 1 ½ hour at 0-5°C. Filter the precipitated solid and washed with ethyl acetate. Methanol (200 ml) was added to the obtained solid and the reaction mixture was heated to 45-50°C. Carbon was added to the reaction mixture and stirred for 15 minutes. Filter the reaction mixture and washed with methanol. Distilled-off the solvent completely from the filtrate and dimethyl formamide (150 ml) was added and stirred at 45-50°C for dissolution. Filter the reaction mixture and the filtrate was cooled to 10-15°C. Water (500 ml) was slowly added to the filtrate over a period of 1 hour at 10-15°C. Filter the precipitated solid and washed with water and then dried to get the title compound. Yield: 70 grams.

Example-12: Preparation of 4-(4-methoxy phenyl) -4-oxobutanoic acid (Formula-11) Succinic anhydride (27.7 g) followed by anisole (30 g) were added to a solution of aluminium chloride (74.4 g) in dichloromethane (300 ml) at 0-5°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was poured into a mixture of ice water and hydrochloric acid. The reaction mixture was stirred for 2 hours at 0-5°C. Filtered the solid, washed with water and then dried to get title compound. Yield: 55 grams.

Example-13: Preparation of 4-(4-methoxy phenyI)butanoic acid (FormuIa-12)

A mixture of 4-(4-methoxyphenyl)-4-oxobutanoic acid compound of formula- 11 (15 g) and triethylsilane (41.46 g) was heated to 40-45°C and then stirred for 4 hours at 40-45°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and added water followed by ethylacetate. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethylacetate. Both the organic layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from organic layer and co-distilled with pet.ether.The reaction mixture was cooled to 25-30°C and pet.ether was added and further cooled to 0-5°C. Filtered the solid, washed with pet.ether and then dried to get the title compound. Yield: 9 grams.

Example- 14: Preparation of 7-methoxy-l-tetralone (Formula-3)

Preparation was similar to the process disclosed in JP 2004182660 A starting from 4-(4-methoxyphenyl)butanoic acid.

Example- 15: Preparation of iV-[2-(7-methoxy-l-naphthyl)ethyI]acetamide (Formula-l)

A solution of DDQ (27 g) in dichloromethane (125 ml) was added to pre-cooled solution of N-(2-(7-methoxy-3 ,4-dihydronaphthalen- 1 -yl)ethyl)acetamide compound of formula-7

(25 g) in dichloromethane (250 ml) at 10-15°C. The reaction mixture temperature was raised to 25-35°C and stirred for 12 hours at at the same temperature. After completion of the reaction, distilled off the solvent from the reaction mixture to obtain residue. The residue was dissolved in dimethylformamide (25 ml) by stirring at 50-55°C. The reaction mixture was cooled to 25-35°C and further cooled to 10-15°C. 2% aqueous sodium hydroxide solution (375 ml) was added to the reaction mixture and stirred for 2 hours at

10-15°C. Filtered the solid and washed with 2% aqueous sodium hydroxide solution.

Dissolved the obtained solid in dimethylformamide (50 ml) by heating the reaction mixture to 50-55°C. Carbon was added to the reaction mixture at 50-55°C and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with dimethylformamide. The filtrate was added to the pre-cooled 2% aqueous sodium hydroxide solution at 10-15°C for a period of 45 minutes. The reaction mixture was stirred for 2 hours at 10-15°C. Filtered the obtained solid, washed with 2% aqueous sodium hydroxide solution and then dried to get title compound. Yield: 17 grams

Example-16: Purification of iV-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (Formula-1) N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) was dissolved in ethylacetate

(50 ml) at 50-55°C. A solution of oxalic acid (11.12 g) in water (50 ml) was added to the reaction mixture at 50-55°C. The reaction mixture was stirred for 30 minutes at 50-55°C. The reaction mixture was cooled to 0-5°C and stirred for 2 hours. Filtered the obtained solid, washed with water and then dried to get N-[2-(7-methoxy- l- naphthyl)ethyl]acetamide oxalate compound of formula-2a. Dichloromethane followed by water were added to the obtained oxalate salt and the pH of the reaction mixture was adjusted to 9.5 with 10% sodium carbonate. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer to obtain N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide as a solid. Dissolved the obtained solid in dimethylformamide (50 ml) and the reaction mixture was heated to 50-55°C for 15 minutes. Further the reaction mixture was cooled to 25-35°C and added to the pre-cooled water (250 ml) at 10-15°C. The reaction mixture was stirred for 2 hours at 10-15°C. Filtered the solid, washed with water and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide crystalline form-I. Yield: 20 grams

Example-17: Preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide oxalate (Formula-2a)

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) was dissolved in ethylacetate (50 ml) at 50-55°C. A solution of oxalic acid (11.12 g) in water (50 ml) was added to the reaction mixture at 50-55°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 0-5°C and stirred for 2 hours at the same temperature. Filtered the obtained solid, washed with water and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide oxalate compound of formula-2a. The obtained N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide oxalate is in the form of co-crystals and its PXRD is depicted in figure-3.

Example-18: Preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide hydrochloride (Formula-2b) A mixture of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) and ethylacetate (50 ml) was cooled to 0-5°C and slowly added ethylacetate-hydrochloride over a period of 30 minutes until pH equals to 2. The reaction mixture was stirred for 60 minutes. Filtered the solid, washed with ethyl acetate and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide hydrochloride. Yield: 16 g

The PXRD of obtained N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide hydrochloride compound of formula-2b of the present invention is depicted in figure-4. Example- 19; Preparation of N-[2-(7-methoxy-l-naphthyi)ethyl]acetamide (Formula-l)

DDQ (27.79 g) was added to a mixture of N-(2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7 (25 g) and toluene (250 ml) under nitrogen atmosphere and heated to 70-75°C. The reaction mixture was stirred

v v for 12 hours at 70-75°C and then cooled to 25-35°C. 2% sodium hydroxide solution was added to the reaction mixture and stirred for 30 minutes at 25-35°C. Both the toluene and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the toluene layers were combined and washed with water. Distilled off the solvent from the toluene layer to get solid. Dissolved the obtained solid in dimethylformamide by heating to 50-55°C. Carbon was added to the reaction mixture and stirred for 10-15 minutes at 50-55°C. Filtered the reaction mixture and washed with dimethylformamide. The filtrate was added to the pre-cooled 2% aqueous sodium hydroxide solution at 10-15°C over a period of 30 minutes and stirred for 2 hours at 10-15°C. Filtered the solid, washed with 2% aqueous NaOH solution and then dried to get title compound. Yield: 17 grams.

ExampIe-20: Purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (Formula-l)

Dissolved the crude N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (10 g) in dimethylformamide by heating to 50-55°C. Carbon was added to the reaction mixture and stirred for 10-15 minutes at 50-55°C and filtered the reaction mixture. The filtrate was added to the pre-cooled 2% aqueous sodium hydroxide solution at 10-15°C over a period of 30 minutes and stirred for 2 hours at 10-15°C. Filtered the solid, washed with 2% aqueous sodium hydroxide solution and then dried to get title compound. Yield: 9 grams. Example-21: Preparation of Form-M of/V-[2-(7-methoxy-l-naphthyl)ethyl] acetamide

5g of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide was dissolved in methyl tertiary butyl ether( 100ml) and heated the reaction mixture to 55-58 °C and stirred for 90 min. Then the reaction mixture was slowly cooled to room temperature and further cooled to 0-5°C. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the precipitated crystals and washed with MTBE. Dried the compound to get the crystalline form-M of N- [2-(7-methoxy-l-naphthyl)ethylJacetamide. Yield: 3grams

Example-22 Preparation of Form-1 of JV- [2 (7 methoxy i~naphthyl)ethyljacetamide 0.01ml of 2-(7-methoxynaphth-l-yl)etylamine is added to 6ml of pyridine. The mixture was cooled in an ice bath with stirring, and 0.012 mol of acetylchloride was added drop wise. The stirring was continued for 30minutes, and then the reaction mass was poured onto ice. The formed precipitate was washed and dried and recrystallized from Isopropyl ether. Yield: 92%

Example-23: Preparation of Form-II of iV-[2-(7-methoxy-l-naphthyI)ethyl] acetamide

Potassium carbonate(2.8g) was added to a solution of 2-(7-methoxynaphth-l- yl)etylamine(2.38g) in water(40ml) and chloroform(60ml).The reaction mixture was cooled to 0° C and was added acetylchloride dropwise at same temperature. The reaction mixture was stirred for 30min at 0°C. The oraga ic layer was separated, washed with water and evaporated under reduced pressure. The obtained residue was crystallized from, toluene/hexane in the ratio of 2: 1 to get the title compound. Yield: 2.0 grams

ExampIe-24: Preparation of Form-M of N-[2-(7-methoxy-l-naphthyl)ethyl] acetamide.

Potassium carbonate(2.8g) was added to a solution of 2-(7-methoxynaphth-l- yl)ethylamine(2.38g) in water(40ml) and chloroform(60ml).The reaction mixture was cooled to 0° C and was added acetylchloride dropwise at same temperature. The reaction mixture was stirred for 30min at 0°C. The organic layer was separated, washed with water and evaporated under reduced pressure. The obtained residue was crystallized from methyl tertiary butyl ether to get the title compound. Yield: 2.0 grams

Claims

We Claim:

1. A crystalline form-M of 2-(7-methoxy-3,4-dihydronaphthalen-l-yI)ethanamine hydrochloride salt compound of formula-6a characterized by its DSC thermogram showing endothermic peak at 151.12°C as illustrated in figure- 1.

2. A crystalline form-S of (E)-2-(7-methoxy-3_s4-dihydronaphthalen-l(2H)-ylidene) ethanamine hydrochloride salt compound of formula-9a characterized by its DSC thermogram showing endothermic peak at 136.87°C as illustrated in figure-2.

3. A process for the preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl) ethanamine compound of formula-5 and/or its acid addition salt compound of general formula-6, comprising of: v

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl) acetonitrile compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of an acid or a base at 45- 60°C to provide 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) optionally, treating the compound of formula-5 with an acid to provide its corresponding acid addition salt compound of general formula-6.

4. A process for the preparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethanamine compound of formula-8 and/or its acid addition salt compound of general formula-9, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy- l,2,3,4-tetrahydronaphthalen-l-yl) acetonitrile compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of an acid or a base at 25- 35°C to provide (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanamine compound of formula-8,

5. A process for the preparation of N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide compound of formula- 1, comprising of: a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a base in a suitable solvent to provide 2-(l-hydroxy-7-methoxy- l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it from a suitable solvent selected from hydrocarbon solvents, ester solvents or mixture thereof to provide pure compound of formula- 4,

b) treating the compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of an acid or a base at 45- 60°C provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5, optionally converting it into its acid addition salt compound of general formula-6 by treating with a suitable acid,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen- l- yl)ethyl)acetamide compound of formula-7,

d) optionally, isolating the compound obtained in step c) form a suitable hydrocarbon solvent or ester solvent to provide compound of formula-7 as a solid,

e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide compound of formula- 1.

6. A process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7- methoxy-l ,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it from a suitable solvent selected from hydrocarbon solvents, ester solvents or mixture thereof to provide pure compound of formula- 4,

b) treating the compound of formula-4 with hydrogen gas in presence of a metal catalyst in a suitable solvent in the presence or absence of an acid or a base at 25- 35°C provides (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanamine compound of formula-8, optionally converting it into its acid addition salt compound of general formula-9 by treating with a suitable acid, c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula- 10,

d) optionally, isolating the compound obtained in step c) from a suitable

hydrocarbon solvent or ether solvent to provide compound of formula- 10 as a solid,

e) aromatizing the compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide

v

compound of formula- 1.

A process according to claims 5 and 6, wherein;

in step a) the suitable base is selected from sodium hexamethyl disilazide, lithium hexamethyl disilazide,

in step b) the metal catalyst is Raney-Ni or Pd/C,

in step-c) the suitable acetylating agent is selected from acetyl halide, acetic anhydride and acetic acid.

A process for the preparation of N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Aromatizing the N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 (or) (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula-!,

b) optionally, purifying the compound obtained in step-a) from a suitable solvent to provide pure compound of formula- 1.

A process for the purification of 2-(l -hydroxy-7-methoxy-l,2,3,4-tetrahydro naphthalen-l-yl)acetonitrile compound of formula-4, comprising of:

a) Dissolving the 2-(l-hydroxy_r7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl) acetonitrile compound of formula-4 in a suitable solvent by heating to higher temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture,

d) filtering the solid to provide pure compound of formula-4.

10. A process according to claim-9, wherein the suitable solvent used in step-a) is selected from cyclohexane solvents, ester solvents or mixtures thereof.

11. A process according to claim- 10, wherein the ester solvents are selected from ethyl acetate, methyl acetate and isopropyl acetate.

12. N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula- 7 as a solid characterized by its DSC thermogram showing endothermic peak at 107.95°C.

13. A process for the preparation of solid N-(2-(7-methoxy-3,4-dihydronaphthalen-l- yl)ethyl)acetamide compound of formula-7, comprising of:

a) Dissolving the N-(2-(7-methoxy-3,4-dihydronaphthalen- 1 -yl)ethyl)acetamide compound of formula-7 in a suitable solvent by heating to higher temperature, b) cooling the reaction mixture,

c) stirring the reaction mixture,

d) filtering the reaction mixture to provide compound of formula-7 as a solid.

14. (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide

compound of formula- 10 as a crystalline solid having melting range of 65-75°C.

15. A process for the preparation of solid (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen- l(2H)-ylidene)ethyl)acetamide compound of formula- 10, comprising of:

a) Dissolving the (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl) acetamide compound of formula- 10 in a suitable solvent at 25-35°C,

b) stirring the reaction mixture,

c) filtering the reaction mixture to provide compound of formula- 10 as a solid.

16. The process according to claims 13 & 15, the suitable solvent used is selected from hydrocarbon solvents, ester solvents and ether solvents.

17. A process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Dissolving the N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide compound of formula- 1 in a suitable solvent by stirring at higher temperature,

b) cooling the reaction mixture,

c) adding aqueous base to the reaction mixture,

d) filtering the precipitated solid and washing with an aqueous base,

f) treating the reaction mixture with carbon,

g) filtering the reaction mixture and washing with a suitable solvent,

h) aqueous base is added to the filtrate and stirring the reaction mixture,

i) filtering the solid and washing with a suitable solvent to get pure N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

18. A process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:

a) Dissolving the N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 in a suitable solvent by stirring at higher temperature,

b) adding aqueous acid solution to the reaction mixture,

c) cooling and stirring the reaction mixture,

d) filtering the precipitated solid and washing with a suitable solvent to get acid addition salt of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of general formula-2,

e) adding a chloro solvent to the solid obtained from step-d),

f) adjusting the pH of the reaction mixture to 9-10 by adding an aqueous base, g) separating the layers and distilling off the solvent from the organic layer to get pure N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.

19. Crystalline form-M of N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide compound of formula- 1

Formula- 1

characterized by its powder X-ray difiractogram having characteristic peaks at 11.20, 11.86, 19.55, 22.51 and 31.91 ± 0.2 degrees of 2Θ.

20. The crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide is further characterized by its powder X-ray difiractogram having peaks at about 11.20, 11.86, 17.54, 18.38, 18.54, 19.55, 19.73, 20.51, 21.78, 22.51, 23.04, 24.60, 25.39 and 31.91 ± 0.2 degrees of 2Θ.

21. A process for the preparation of novel crystalline form-M of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide comprising of the following steps;

a) Dissolving the N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide compound of formula- 1 in a suitable organic solvent selected from ketone solvents, ether solvents and alcoholic solvents, preferably ether solvents like methyl tertiary butyl ether.

b) heating the reaction mixture to 55° C to 80° C, preferably 65°C to 75°C and stirring,

c) cooling the reaction mixture to room temperature,

d) further cooling the reaction mixture to 0-5° C and stirring,

e) filtering the precipitated solid and washing with a suitable organic solvent, f) drying the solid to get the crystalline form-M of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide.

22. A process for the preparation of novel crystalline form-M of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide comprising of the following steps;

a) Dissolving the N-[2-(7-methoxy- l-naphthyl)ethyl]acetamide compound of formula- 1 in methyl tertiary butyl ether,

b) heating the reaction mixture to 65-75°C and stirring for 90 min,

c) cooling the reaction mixture to room temperature, d) further cooling the reaction mixture to 0-5° C and stirring for 2 hrs,

e) filtering the precipitated solid and washing with methyl tertiary butyl ether, f) drying the solid at 55-65°C for 12-14 hrs to get crystalline form-M of N-[2-(7- methoxy- 1 -naphthyl)ethyl] acetamide.

23. A process for the preparation of crystaline N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide comprises of recrystallization of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide from a suitable organic solvent selected from ether solvents or ketone solvents.

24. A process according to claim 23, wherein the organic solvent used for recrystallization of N-[2-(7-methoxy-l-naphthyl)ethyl] acetamide is methyl tertiary butyl ether.

25. A process according to the preceding claims, the N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide having the purity of 99.5, preferably 99.75, more preferably 99.90 by HPLC.

26. Use of crystalline 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a in the preparation of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide of formula- 1.

27. Use of crystalline (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanamine hydrochloride salt compound of formula-9a in the preparation of N-[2-(7- methoxy-l -naphthyl)ethyl]acetamide of formula- 1.

28. Use of crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide as an active pharmaceutical ingredient in the preparation of pharmaceutical composition.

Dated this day of October 2011.

Authorized S gnatory

(SrinivasanThirumalaiRaj an)

MSN Laboratories Limited.