WO2015022702A2

WO2015022702A2 - Process for preparation of 4,5-dimethoxybenzene derivatives and use in the synthesis of ivabradine and salts thereof

Info

Publication number: WO2015022702A2
Application number: PCT/IN2014/000522
Authority: WO
Inventors: Rajesh Vinodrai Naik; Gurdeep Singh Sarin; Pranav Gupta; Dilpreet Singh
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2013-08-10
Filing date: 2014-08-11
Publication date: 2015-02-19
Also published as: WO2015022702A3

Abstract

The present invention relates to an improved process for preparation of 4,5-dimethoxybenzene derivatives, which are important key intermediates in the preparation of ivabradine and salts thereof. Mainly present invention relates to an efficient and industrially advantageous process for purification of 4,5-dimethoxy benzocyclbbutane derivatives, which are important key intermediates in the preparation of ivabradine and salts thereof. Particularly, the present invention relates to a process for purification of 4,5-dimethoxy- 1-cyano-benzocyclobutane of formula I, and a process for purification of (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N- (methyl)amine camphosulphonic acid salt of formula II. The present invention also relates to an efficient and industrially advantageous process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III, with high purity and high yield, wherein compound of formula III is an important precursor of 4,5-dimethoxy- 1-cyano-benzocyclobutane of formula I, a key intermediate used in the preparation of ivabradine and salts thereof.

Description

TITLE OF THE INVENTION

Process for preparation of 4,5-ditnethoxybenzene derivatives and use in the synthesis of ivabradine and salts thereof.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of 4,5-dimethoxybenzene derivatives, which are important key intermediates in the preparation of ivabradine and salts thereof. Mainly present invention relates to an efficient and industrially advantageous process for purification of 4,5-dimethoxy benzocyclobutane derivatives, which are important key intermediates in the preparation of ivabradine and salts thereof.

Particularly, the present invention relates to a process for purification of 4,5-dimethoxy- 1 - cyano-benzocyclobutane of formula I,

Formula I

and a process for purification of (S)-N-[(4,5-dimethoxybenzocyclobut- l -yl)-methyl]-N-

(methyl)amine camphosulphonic acid salt of formula II.

Formula II

The present invention also relates to an efficient and industrially advantageous process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III, with high purity and high yield, wherein compound of formula III is an important precursor of 4,5-dimefhoxy-

1-cyano-benzocyclobutane of formula I, a key intermediate used in the preparation of ivabradine.

Formula III

BACKGROUND OF THE INVENTION

Ivabradine and its pharmaceutically acceptable salts have very valuable pharmacological and therapeutic properties and is chemically known as (5)-7,8-dimethoxy-3-{3-{N-[(4,5- dimethoxybenzocyclobut- l-yl)methyl-N-(methyl)aminp)propyl) l ,3,4,5-tetrahydro-2H- 3- benz azepine-2-one and structural formula is as shown below :

It is useful in many cardiovascular diseases such as angina pectoris, myocardial infraction and associated rhythm . disturbances. Ivabradine and its pharmaceutically acceptable salts are first disclosed in US patent 5,296,482. The patent also discloses a process for preparation of ivabradine hydrochloride through 4,5-dimethoxy-l-cyano-benzocyclobutane intermediate, as shown below in scheme 1.

SCHEME !

As represented in scheme 1 , ivabradine hydrochloride is prepared by reduction of 4,5- ^' dimethoxy-l-cyano-benzoeyclobutane with boron-tetrahydrofuran complex to form 4,5^ dimethoxy-1 -(methyl amine)-benzocyclobutane; which upon condensation with ethylchloro formate and further reduction with lithium aluminium hydride . in tettahydrofuran resulted in racemic methyl amine derivative. The racemic compound is resolved with camphosulphonic acid in ethanol to form enantiomeric methyl amine camphosulphonic acid salt, which is recrystallised first in ethyl acetate and then in acetonitrile. The resulting methyl amine camphosulphonic acid salt is further hydrolyzed using a base to form methyl amine derivative, which is then condensed with 7,8-dimethoxy-3-[3-iodopropyl]- l,3-dihydro-2H-3- benzazepine-2-one in the presence of a base such as potassium carbonate in acetone. The resulting benzazepine intermediate is purified by column chromatography and is further reduced with palladium hydroxide in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine which is converted into its hydrochloride salt by action of aqueous hydrochloric acid.

It has been observed that said process suffers from several drawbacks such as purification of methyl amine camphosulphonic acid salt derivative using ethyl acetate and acetonitrile which results in lower yield and low efficiency. Further purification using expensive and toxic acetonitrile as solvent, which is tedious in handling and making the process time consuming and difficult to utilize on an industrial scale. ⁵

The patent also discloses 4 -5-dimethoxy-l -cyano-benzocyclobutane intermediate can be prepared from 3-(2-bromo-4,5-dimethoxy-benzene)prdpionitrile. The processes of preparation of 4,5-dimethoxy- l -cyano-benzo cyclobutane intermediate . and its precursor 3-(2-bromo-4,5- dimethoxy benzene) propionitrile intermediate have not been mentioned in this patent.

There are several methods reported in literature, wherein processes of preparation of 3-(2- bromo-4,5-dimethoxybenzene)propionitrile intermediate, 4,5-dimefhoxy- 1 -cyanobenzo cyclobutane and (S)-N-[(4,5-dimethoxybenzocyclobut- l -yl)-methyl]-N-(methyl)amine derivative and purifications have been disclosed and are discussed herein.

US patent 8, 198,485 discloses resolution of methyl amine derivative by using di-p-toluoyl-L- tartaric acid salt.

A PCT publication WO2008/065681 discloses a process for the preparation of ivabradine and its pharmaceutically acceptable salts · by using intermediate (S)- V-[(4,5- dimethoxyberizocyclobut-l -yl)-methyl |-N-(methyl)amine camphosulphonic acid salt, which is prepared by reacting methyl amine derivative with camphosulphonic acid in isopropyl alcohol and the isolated solid is washed with isopropyl alcohol to yield a novel crystalline form. This PCT application is silent about the purity and yield of camphosulphonic acid salt of methyl amine derivative.

Another PCT publication WO201 0/072409 discloses resolution of methyl amine derivative by using mandelic acid salt.

Another PCT publication WO201 1 /138625 discloses a process for preparation of 4,5- dimethoxy- l -cyano-benzocyclobutane, by reacting 2-bromo-4,5-dimethoxyphenylpropionitrile dissolved in anhydrous tetrahydrofuran was added in solution of LDA, and the resulting anion undergoes facile intramolecular cyclization that yields the desired intermediate which is then washed with ethanol. The above patent application is completely silent about purity and assay of resulting cyano intermediate. An article, namely J Org. Chem 1972 (37) pp.3374-3376, discloses a process for the preparation of 4, 5-dimethoxy-l -cyano-benzocyclobutane, wherein 2-½omo-4,5- dimethoxyphenylpropionitrile under goes facile intramolecular cyclization in the presence of potassium amide. After the reaction is over, then reaction mass is treated with ammonium nitrate for neutralization, and the residue, thus formed, is treated with a mixture of chloroform and water and washed with saturated aqueous sodium chloride solution and filtered. The filtrate is concentrated to viscous oil and eluted with chloroform through column containing acid washed alumina. The product is isolated as white powder further recrystallisation from hexane. The main drawback of the process is that the chromatographic technique for purification is cumbersome, tedious and difficult to utilize on an industrial scale.

Further, process for the preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile,

dimethoxyphenyl propionitrile in overall yield of 48%.

The main drawback of this process is that it is highly time consuming, uses toxic reagents, results in low yield and is also silent about the purity of 3-(2-bromo-4,5- dimethoxybenzene)propionitrile.

Another article, namely Tetrahedron 1973 (29) pp. 73-76 discloses a process for preparation of 4,5-dimethoxy- 1 -cyano-benzocyclobutane, wherein 2-bromo-4,5-dimethoxyphenylpropionitrile is reacted with a solution of sodium amide at room temperature for 2 hours, treatment with ammonium chloride and water yields grey crystal. Which are further recrystallized from ethanol to produce colorless crystals of desired intermediate. The above article is completely silent about purity and assay of resulting 4,5-dimethoxy- 1 -cyano-benzocyclobutane. Further, process . for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile, precursor of 4,5- dimethoxy- 1 -cyano-benzocyclobutane, is also disclosed as shown in below scheme, wherein 2-bromo-4,5-dimethoxybenzaldehyde was reacted with cyanoacetic acid in the presence of ammonium acetate, beiizene, pyridine and the reaction mixture is heated under reflux to form pyridine salt of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-acfylic acid. In a solution of pyridine salt of resulting intermediate, sodium bicarbonate and sodium borohydride are added and then reaction mixture is acidified with hydrochloric acid to yield 3-(2-bromo-4,5- dimethoxyphenyl)-cyanopropionic acid.

37%. The said process is not attract ve rom commerc a po nt o v ew, e ng very ow

'^'

The process comprises condensation of 2-bromo-4,5-dimefhoxybenzaldehyde with acetonitrile in the presence of sodium hydroxide to give 2-bromo-4,5-dimemoxycinnamonitrile and the resulting compound, was reduced using sodium borohydride in a mixture of ethanol and pyridine After completion of reaction, the reaction mass was cooled to room temperature and acidified with hydrochloric acid (10%). The. product was extracted with ethylacetate, the organic layer was separated, washed with water and dried. The solvent was evaporated and the resulting residue was recrystallized from ethanol. Further resulting compound 3-(2-bromo-4,5- dimethoxybenzene) propionitrile is converted into 4,5-dimethoxy-l-cyano-benzocyclobutane through intramolecular cyclization.

The above process also suffers from several drawbacks like use of pyridine, which is toxic in nature and have very bad odor, further process is also lengthy, costly, results in low yield.

A Chinese patent CN 101407474B also discloses a process similar to that reported in Journal of Chemical Research 2009, pp. 420-422, for preparation of 3-(2-bromo-4,5- dimethoxybenzene) propionitrile with some minor changes by avoiding use of pyridine and results in overall yield of 55-58.0% of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile, and is silent about the purity of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile. Further, conversion of 3-(2-bromo-4,5-dimethoxy benzene) propionitrile into 4,5-dimethoxy-l -cyano- benzocyclobutan has not been disclosed.

Like any synthetic compound, intermediate compounds can contain extraneous compounds or impurities that can come from many sources which may get carried forward to final API i.e. ivabradine or pharmaceutically acceptable salt thereof or may react to form other by products. These extraneous compounds in the intermediate may be unreacted starting materials, by products of the reaction, products of side reactions, or degradation products or different isomers. Impurities generated due to any reason in any active pharmaceutical ingredient (API) like ivabradine and salt thereof are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing API.

Moreover, impurities introduced during commercial manufacturing processes must be limited to very small amounts, and should preferably the substantially absent. For example, ICH Q7A guidance for manufacturers states that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratio, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. - It is always advantageous to use intermediates of high purity and free from the undesired impurities or such impurities should be present in acceptable amounts 4,5-dimethoxy-l-cyano- benzo cyclobutane, is a key intermediate for the synthesis of ivabradine hydrochloride. The purity of the chemical compounds can be measured by chromatographic techniques such as high pressure liquid chromatography (HPLC). Purity of a compound as measured by HPLC is relative purity of the compound with respect to the presence of organic impurities. The impurities present are measured in the presence of the desired material. HPLC purity of the chemical compound does not provide any indication about the inorganic impurities present in the compound. Therefore determination of assay of the chemical compound is as important, as that of purity of the compound, which gives clear indication about the actual content of the desired compound present in a sample. Assay is different from the purity. Assay provides an exact result of the content or potency of the analyte in a sample. A product having 99% purity can even have assay 99% or as low as even 40%. Therefore, to provide the final API i.e. ivabradine or pharmaceutically acceptable salt thereof, in high purity and to make sure that is should be free from organic as well as inorganic impurities, the determination of assay of the

. intermediates before proceeding to next. stage is also very important. It is found by the present inventor that 4,5-dimethoxy-l-cyano-benzocyclobutane prepared by prior art processes followed by simple recrystallization is not pure, may be due to presence of inorganic impurities along with other undesired impurities.

As most of the prior art processes are- silent about purity and assay of the cyano intermediate, there is an urgent need to develop a process which provides high content of the intermediate (assay) as well as high purity to ensure the high potency of the final API i.e. ivabradine or pharmaceutically acceptable salt thereof, which is free from the undesired organic as well as inorganic impurities or other impurities are present in acceptable amounts. Thus, the present invention provides a process for the purification of cyano intermediate of formula I, which makes the intermediate suitable synthesizing ivabradine or pharmaceutically acceptable salt thereof of high in purity & potency.

The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by products of the reaction and adjunct reagents used in the reaction, can also be present in the product mixture. At certain stages, during processing of an intermediate, it must be analyzed for purity, typically by TLC or HPLC analysis, to determine if it is suitable for continued processing and ultimately for use in a preparation of final API. The final API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standard are set with the intention of ensuring^' that an API is as free of impurities as possible, and thus, is as safe as possible for clinical use.

In view of the above, there is an urgent need to develop an efficient, cost effective, industrially viable process for the synthesis of pure 3-(2-bromo-4,-5-dimethoxybenzene) propionitrile in high yield and high purity, because it is an important precursor of l-cyano-4,5- dimethoxybenzo cyclobutane, which in turn is a key intermediate, in the preparation of ivabradine or pharmaceutically acceptable salt thereof. Therefore, there is a need to^provide an efficient and industrially advantageous process of purification of intermediates of ivabradine, which curtail the presence of impurities or make it free from impurities and parallel there should be improvement in yield.

OBJECT OF THE INVENTION

The .main object of the present invention is to provide an efficient and industrially advantageous process for the purification of 4,5-dimethoxy benzocyclobutane derivatives, important intermediates of ivabradine and salt thereof.

Another object of present invention is to provide an improved process for purification of 4,5- dimethoxy- 1-cyaho-benzocyclobutane of formula I having improved assay and purity.

Another object of the present invention is to provide a process for preparation of boc protected intermediate of formula V, which can be optionally crystallize and filter to obtain high level of purity. , ·

Another object of present invention is to provide an improved process for purification of (S)-N- [(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl)amine camphosulphonic acid salt of formula II, having improved purity and yield.

Another object of present invention is to provide an improved process for purification of (S)-iV- [(4,5-dimethoxybenzocyclobut-l -yi)-methyl |-N-(methyl)amine camphosulphonic acid salt of formula II by avoiding use of toxic and expensive solvent.

Another object of present invention is to provide an improved process for preparation of pure ivabradine or pharmaceutically acceptable salt thereof using highly pure 4,5-dimethoxybenzene derivatives.

Another object of the present invention is to provide an efficient and industrially advantageous one pot process for the preparation of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile, precursor of .l -cyano-4,5-dimethoxybenzocyclobutane which is a key intermediate in the preparation of ivabradine or pharmaceutically acceptable salt thereof.

Another object of the present invention provides a process for the preparation of 3-(2-bromo- 4,5-dimethoxybenzene)propionitrile in high purity and high yield,

Another object of the present invention provides an one pot process for the preparation of 3-(2- bromo-4,5-dimethoxybenzene)propionitrile in high purity and high yield.

Another object of the present invention provides a process for preparation of l -cyano-4,5-di methoxybenzocyclobutane by employing highly pure 3-(2-bromo-4,5-dimefhoxybenzene) propionitrile.

Another object of the present invention provides a process for the preparation of ivabradine by employing highly pure 3-(2-bromo-4,5-dimethoxybenzene) propionitrile.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for preparation of highly pure 4,5- dimethoxybenzene derivatives. ·^■ ·

Mainly present invention provides an one pot process for the preparation of 3-(2-bromo-4,5- dimethoxybenzene)propionitrile in high purity and high yield and purification of 4,5- dimethoxy benzocyclobutane derivatives, which are important intermediates in the preparation of ivabradine or pharmaceutically acceptable salt thereof.

According to embodiment I, the present invention provides a process for purification of 4,5- dimethoxy- 1 -cyano-benzocyclobutane of formula I.

Formula I

which is an important intermediate in the preparation of ivabradine or pharmaceutically acceptable salt thereof.

According to embodiment 2, the present invention provides a process for purification of 4,5- dimethoxy-1 -cyano-benzocyclobutane of formula I, comprising the steps of:

a) providing a solution of crude cyano intermediate of formula 1, in an aromatic hydrocarbon solvent; ^'

b) adding silica gel and / or activated carbon to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours; d) filtering the reaction mass;

e) distilling , off the solvent;

f) adding aliphatic hydrocarbon solvent to the resulting reaction mass;

g) heating the reaction mass at reflux temperature;

h) cooling the resulting mixture; and

i) isolating pure 4, 5-dimethoxy-l-cyano-benzocyclobutarie of formula I.

According to embodiment 3, the present invention provides a process for purification of 4,5- dimethoxy-l-cyano-benzocyclobutane of formula I, comprising the steps of:

a) providing a solution of crude cyano intermediate of formula 1, in an aromatic hydrocarbon solvent;

b) adding silica gel and / or activated carbon to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) , filtering the reaction mass;

e) distilling off the solvent;

f) optionally, adding aliphatic hydrocarbon solvent to the resulting reaction mass;

g) optionally, heating the reaction mass at reflux temperature;

h) optionally, cooling the resulting mixture; and

i) isolating pure 4,5-dimethoxy-l -cyano-benzocyclobutane of formula ΐ.

According to embodiment 4, present invention provides a process for the preparation of ivabradine or pharmaceutically acceptable salt thereof, comprising the steps of

a) providing a solution of crude cyano intermediate of .formula I, in an aromatic hydrocarbon solvent; _: - b) adding silica gel and / or activated carbon to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) filtering the reaction mass;

e) distilling off the solvent;

f) adding aliphatic hydrocarbon solvent to the resulting reaction mass;

g) heating the reaction mass at reflux temperature;

h) cooling the resulting mixture;

i) isolating pure 4, 5-dimethoxy- l-cyario-benzocyclobutane of formula I; and

j) converting pure 4,5-dimethoxy-l -cyano-benzocyclobutane of formula I in to ivabradine or pharmaceutically acceptable salt thereof. According to embodiments 5* present invention provides a process for purification of (S)-7V- [(4,5-dimethoxybenzocyclobut- l -yl)-rnethyl]-N-(methyl)amine camphosulphonic acid salt of formula II.

Formula II

which is a key intermediate in the preparation of ivabradine or pharmaceutically acceptable salt thereof.

According to embodiment 6, the present invention provides a process for purification of (S)-7V- [(4,5-dimethoxybenzocyclobut-l -yl)-methyl]-N-(methyl)amine camphosulphonic acid salt of formula II, comprising the steps of:

a) providing a solution of crude camphosulphonic acid salt of formula II in an alcoholic solvent;

b) adding an ether as antisolvent slowly to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) cooling the resulting mixture; and ·

e) isolating pure camphosulphonic acid salt of formula II.

According to embodiment 7, present invention provides a process for the preparation of ivabradine or pharmaceutically acceptable salt thereof, comprising the steps of

b) adding an ether as antisolvent slowly to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) cooling the resulting mixture;

e) isolating pure camphosulphonic acid salt of formula II; and

f) converting pure methyl amine camphosulphonic acid intermediate in to ivabradine or pharmaceutically acceptable salt thereof.

According to embodiment 8, the present invention provides a novel, convenient, industrially advantageous and efficient process for preparation of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula III,

Formula III

comprises the steps of: a) reacting 2-bromo-4,5-dimethoxybenzaldehyde of formula VII,

Formula VII

with alkyl cyano derivative of formula VIII,

Formula VIII

wherein R is selected from -COOR' and R' is H, or an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, .n-butyl or ter-butyl or alike,

in the presence of a suitable base in a suitable solvent to form cyano-acrylic acid compound of formula IX,

Formula IX

b) reducing in-situ cyano-acrylic acid compound of formula VIII using a suitable reducing agent in the presence of a suitable base and a suitable solvent to obtain cyano-propionic acid compound of formula X ,

Formula X

c) decarboxylating in-situ the resulting cyano-propionic acid compound of formula X, in the presence of a suitable catalyst and a suitable solvent to form 3-(2-bromo-4,5-dimethoxy benzene)propionitrile of formula III .

d) optionally crystallizing 3-(2-biOmo-4,5-dimethoxybenzene)propionitrile of formula III with a suitable solvent,

wherein corresponding cyano compounds of formulae IX and X are not isolated.

According to embodiment 9, the present invention provides a process for preparation of 3-(2- bromo-4,5-dimethoxybenzene)propionitrile of formula III, which comprises the steps:

a) reacting 2-bromo-4,5-dimethoxybenzaldehyde of formula VII,

Formula VII

with alkyl cyano derivative of formula VIII,

Formula VIII

wherein R is selected from -COOR' and R' is H, or an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or ter-butyl or alike,

in the presence of a suitable base in a suitable solvent to form cyano-acrylic acid compound of

Formula IX

b) decarboxylating in-situ the resulting cyano-acrylic acid compound of formula IX in the presence of a suitable catalyst and a suitable solvent to form- 2-bromo-4,5- dimethoxycinnamonitrile compound of formula XI,

Formula ΧΓ

c) reducing in-situ cinnamonitrile compound of formula XI using a suitable reducing agent in the presence of a suitable base and a suitable , solvent to obtain 3-(2-bromo-4,5- dimethoxybenzene)propionitrile of formula III.

d) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III with a suitable solvent,

wherein corresponding , cyano compounds of formulae IX and XI are not isolated.

According to embodiment 10, the present invention provides a process for preparation of 3-(2- bromo-4,5-dimethoxybenzene)propionitrile of formula III, which comprises of decarboxylating 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-propionic acid compound of formula IX in the presence of a suitable catalyst and a suitable solvent to form -3-(2-bromo-4,5- dimethoxybenzene)propionitrile of formula III.

According to embodiment 11 , the present invention provides a process for preparation of 3-(2- bromo-4,5-dimethoxybenzene)propionitrile compound of formula III with high yield and purity comprises of conversion of 2-bromo-4,5-dimethoxy benzaldehyde into 3-(2-bromo-4,5- dimethoxy benzene)propionitrile compound of formula III.

According to embodiment 12, the present invention provides a process for preparation of 1 - cyano-4,5-dimethoxybenzocyclobutane by employing highly pure 3-(2-bromo-4,5- dimethoxybenzene) propionitrile.

According to embodiment 13, the present invention provides a process for the preparation of ivabradine by employing highly pure 3-(2-bromo-4,5-dimethoxybenzene) propionitrile. According to embodiment 14, the present invention provides a process for preparation of ivabradine with high yield and purity, comprising of isolation of any of intermediates, such as cyano-acrylic acid compound of formula IX or cyano propanoic acid compound of formula X or cinnamonitrile compound of formula XI or isolation of all the intermediates and followed by their transformation into ivabradine or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of highly pure 4,5-dimethoxybenzene derivatives. Mainly, the present invention provides an one pot process for the preparation of 3- (2-bromo-4,5-dimethoxybenzene)propionitrile in high purity and high yield and process for purification of 4,5-dimefhoxy benzocyelobutane derivatives, which are important intermediates in the preparation of ivabradine or pharmaceutically acceptable salts thereof.

According to one other embodiment, the present invention provides a process for purification of intermediate compound of formula I, to reduce amount of inorganic as well as highly polar polymeric impurities as well as other impurities and to increase its assay.

According to one other embodiment, the present invention provides a process for purification of intermediate compound of formula I, by adsorbing the impurities On silica gel by using a suitable solvent.

Generally, the process of purification involves dissolving of intermediate compound formula I in an aromatic hydrocarbon solvent. Dissolution of intermediate compound formula I can be achieved at ambient temperature and above depending upon amount of solvent used. Aromatic hydrocarbon solvent such as benzene, toluene, xylene, and the like; of which toluene is preferred. Thereafter reaction solution is treated with silica gel and activated carbon together or independently. Purpose of adding silica gel is to adsorb inorganic impurities as well as polar polymeric impurities and activated carbon for color improvement. The reaction mixture containing silica gel and/or activated carbon can be stirred at heating temperature for 0.5 hour to 12 hours. Heating temperature can be in the range of 35 °C to 90 °C, preferably 45 °C to 80 °C, more preferably 55 °C to 70 °C. Thereafter reaction mass is filtered through hyflo bed and bed can be washed with same aromatic hydrocarbon solvent, which is used during reaction. The solvent collected can be distilled off completely or partially under reduced pressure; preferably it is distilled off completely. After that, anti solvent is added to resulting reaction mass, preferably anti solvent is added slowly to the reaction mass and heated for 30 minute to 6 hours. Anti solvent can be selected from aliphatic hydrocarbon solvent, such as hexane, heptane, cyclohexane and the like; of which hexane is preferred. The reaction mass can be heated up to reflux temperature of antisolvent and further cooled to below room temperature, preferably below 15 °C and more preferably between 0-5 °C and stirred at same temperature for 30 minute to 6 hours. The resulting solid was filtered and washed with aliphatic hydrocarbon solvent and dried to afford pure product.

This purification process involving use of silica gel in a suitable solvent, leads to removal of inorganic impurities as well as polar and few other impurities and improves assay, as compared to purification processes disclosed in prior art:

The purification process as described in the present invention can be repeated to enhance the purity and content of desired intermediate (assay); and to minimize the presence of undesired organic as well as inorganic as well as polar and other impurities present in the compound; or to make it free from impurities. Specifically, the purification process can be repeated to increase the purity as well as assay of intermediate compound of formula I till the desired level of assay and purity is achieved.

The . purified 4,5-dimethoxy-l-cyano-benzocyclobutane of formula I, is highly pure and displays comparatively high percentage of assay. The intermediate may have purity more tha 90%, preferably more than 95%, more preferably 99.9% by HPLC. The intermediate thus obtained may have assay more than 90% w/w, more preferably more than 95% w/w and more preferably 99% w/w However, it is advantageous to proceed further with intermediate of formula I, having purity more than 99% and assay more than 95% w/w, by HPLC to obtain ivabradine or pharmaceutically acceptable salts thereof in high purity having undesired impurities in acceptable amounts or free from the impurities.

In one other embodiment, pure 4,5-dimethoxy-l -cyano-benzocyclobutane of formula I is converted into pure ivabradine or pharmaceutically acceptable salts thereof.

In one other embodiment, the present invention provides a process for purification of camphOsulphonic acid salt of formula II, to minimize amount of impurities and to increase chiral as well as chemical purity and to improve the yield. >

The present invention involves use of a suitable solvent /antisolvent combination for purification of camphosulphonic acid salt of methyl amine intermediate, represented by formula II. The solvent used in the purification can be selected from aliphatic ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate and the like; C|-C₆ alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ter-butanol and the like; and the like; C₃ -C₆ aliphatic ketonic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; C₂ -C aliphatic nitrile solvents such as acetonitrile, propionitrile and the like; of which methanol is preferred. The antisol vent used during purification can be selected from ether solvent such as diethyl ether,_, isopropyl ether, tertiary butyl methyl ether (MTBE), tetrahydrofuran, dioxane and the like; C5-C 10 cyclic or acyclic saturated hydrocarbon solvent such, as hexane, heptane, cyclohexane and the like or mixture thereof; of which tert- butyl methyl ether is preferred.

The present invention demonstrates that the diastereomeric salt can be precipitated from the solution by the use of an antisolvent. The term "antisolvent" may pertain in particular to a fluid that, when added to a solution of a compound, to be precipitated,, induces a partial or complete precipitation of desired compound. Preferably, an antisolvent induces a compound to get precipitated from the solution, in a greater amount and/ or within a shorter period of time, than the compound to be precipitated from . a solution containing an equal concentration of. the compound, to be precipitated from same solvent, when the solution is maintained under the same conditions, however without antisolvent addition.

According to one preferred embodiment, the present invention provides a process foi^¬ purification of (S)-N-[(4,5-dimethoxybenzocyclobut-l -yl)-methyl]-N^:(methyl)amine camphosulphonic acid salt of formula Π, using a mixture of alcoholic solvent and ether as antisolvent.

Generally, the process involves stirring of camphosulphonic acid salt of formula II in alcoholic solvent by heating above ambient temperature to reflux temperature of solvent used, for 15 minute to 24 hours, followed by addition of ether solvent slowly to the reaction mass. Ether can be added to reaction mass at a temperature of 0 °C to reflux temperature. The resulting reaction mass can be further refluxed for 10 minute to 2 hours. Thereafter reaction mass is cooled to 30- 35 °C and stirred for 15 minutes to 4 hours at same temperature. The purified product can be isolated from reaction mixture using a suitable technique such as filtration, centrifugation, decantation and the like.

The camphosulphonic acid salt of formula II, thus isolated is washed with a mixture of suitable solvent like alcoholic solvent and aliphatic ether. The alcoholic solvent and aliphatic ether can be used in a ratio of 1 :5 to 1 :50, preferably 1 :20, more preferably 1 :8. This purification process involving use of mixture of solvents, leads to removal of undesired chiral impurity and improves in yield, hence it is a much superior process, as compare to purification processes disclosed in prior art.

The purification process can be optionally, repeated to achieve desired chiral purity level of camphosulphonic acid salt of. formula II and having minimum amount of impurities. AH impurities have potential to further react in usual reaction sequence leading the final API i.e.^' ivabradine or pharmaceutically acceptable salts thereof.

Therefore, the present invention provides an efficient process for. the purification of camphosulphonic acid salt of formula II, which avoids loss of material caused by purification in the final step. Use of enantiomerically pure camphosulphonic acid salt of formula II, avoids the possibility of generation of more impurities in final product and thus lead to final API i.e. ivabradine or pharmaceutically acceptable salts thereof with high purity.

In one other embodiments, the invention provides an improved process for the preparation of pure (S)-N-[(4,5-dimefhoxybenzocyclobut- 1 -yl)-methyl]-N-(methyl)amine camphosulphonic acid salt of formula II,

Generally, the process comprises reduction of pure 4,5-dimethoxy- l -cyano-benzocyclobutane of formula I, in the presence of catalyst, a base in a suitable solvent to form 4,5-dimethoxy- l - (methyl amine)-benzocyclobutane compound of formula IV,

Formula TV

protecting the intermediate of formula IV with boc anhydride in the presence of a suitable solvent to form intermediate of formula V, Formula V

reducing the intermediate of formula V with a suitable catalyst and in the presence of a suitable solvent to form racemic methyl amine derivative of formula VI, Formula VI

re ethyl amine intermediate of formula VI with camphosulphonic acid

in the presence of suitable solvent to form racemic (S)-N-[(4,5-dimethoxybenzocyclobut- l -yl)- methyl]-N-(me_.thyl)amine camphosulphonic acid salt, puri fying crude CSA salt, by using a suitable_. solvent or mixture thereof to isolate enantiomerically pure CSA salt of formula II. Enantiomerically as well as chemically pure camphosulphonic acid salt of formula II is used to prepare pure ivabradine or pharmaceutically acceptable salts thereof by using the process reported in prior art.

Generally, amino compound of formula IV is prepared by reducing pure compound of formula

I in the presence of catalyst, a base and suitable solvent. The base can be selected from the inorganic base or organic base. Inorganic base such can be selected from an. alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate salt such as sodium carbonate, potassium carbonate, cesium carbonate and the like, of which an alkali metal hydroxide is preferred. Organic base can be selected from bases like Lewis base, trialkylamines such as triethylamine, diisopropylethylamine; and ammonia and the like, of which ammonia is preferred.

The catalyst used in hydrogenation reaction can be selected from any reducing agent capable o performing the same function. Preferably catalyst can be selected from Raney nickel, Pd/C, Pt/C and the like; of which Raney nickel preferred.

The solvent used in reaction can be selected from the group comprising lower C|-C₆ alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like; of which, methanol is preferred.

The hydrogenation reaction can be carried out in an autoclave under 4.0-5.0 kg/cm hydrogen pressure for 30 minutes to 24 hours, preferably for 1 - 10 hours, more preferably till the completion of the reaction. The reaction mass is filter through hyflo bed and the bed is washed with solvent to remove the catalyst. Solvent can be distilled off completely under reduced pressure to get oily liquid. Which is dissolved in water immiscible solvents such as methylene dichloride, chloroform, carbon tetrachloride and the like, of - which methylene dichloride preferred and washed with DM water to remove the impurities. Solvent . can be distilled off completely and oily residue degassed under reduced pressure.

In one another embodiment, the invention involves protecting amino intermediate of formula IV with boc anhydride in the presence of a suitable solvent to form intermediate of formula V. The solvent used during the protection, can be selected from halogenated solvents such as methylene dichloride, chloroform, carbon tetrachloride and the like; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,2-dimefhyl ether, ,2-diethy ether, disopropylether, tertiary butyl methyl ether and the like. .

The reaction can be carried out from 0 °C to boiling point of a used solvent for 15 minutes to 4 hours, preferably till the completion of the reaction. DM water is added to the reaction mass and separation of layers. The organic layer is washed with DM water and solvent is distilled off. Thereafter, aliphatic hydrocarbon solvent is added such as hexane, heptane, cyclohexane and the like, of which hexane is preferred. And solvent is distilled off under reduced pressure. Boc protected intermediate compound of formula V formed can be isolated from reaction mixture or can be insitu converted to compound of formula VI. In one another embodiment, the present invention involves reduction of boc protected amino intermediate of formula V using a suitable catalyst in the presence of a suitable solvent to form of corresponding methyl amine compound of formula VI.

The reducing agent can be selected, from group comprising hydrides such as lithium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, vitride and the like; of which lithium aluminium hydride and vitride are preferred.

The solvent used in reaction can be selected from the group comprising ether solvents such as diethyl ether, propyl ether, butyl ether, tetrahydrofuran, dioxane, 2-mefhyl tetrahydrofuran, 1,2- dimethylether, 1,2-diefhylether; aromatic-' hydrocarbon solvents such as benzene, xylene, toluene and the like. · . . ^■ '

The reaction can be carried out at ambient temperature to reflux temperature of solvent employed for 15 minutes to 4 hours, preferably till the completion of the reaction. Thereafter, the reaction mass is cooled to -5 °C to 10 °C and further treated with dimineralized water. Dimineralized water (DM water) is slowly added at 0-15 °C followed by addition of aqueous sodium hydroxide solution, further reaction mass is stirred at 10 °C to 45 °C for 15 minutes to 4 hours, Thereafter, filter the reaction mass through hyflo bed and bed can be washed with solvent to remove the catalyst. Solvent can be distilled off completely and degassed under reduced pressure to obtain the desired product.

The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC) ultra- highpressure liquid chromatography (UPLC), and the like.

It has been observed that reduction of boc protected amino intermediate of formula V using vitride in the presence of a suitable solvent proves to be best, since it is safer in handling and more convenient to use. Therefore, it is advantageous to make use of vitride, as reducing agent because it is very easy to handle, more stable, non-pyrophoric, cost effective, as . compared to other reducing agents. Additionally, the yield and purity of resulting methyl amine compound of formula VI by using vitride solution is better than those obtained by using other reducing agents.

In one another embodiment, of the invention involves reacting intermediate of formula VI with camphosulphonic acid salt ( CSA salt) in the presence of solvent to form camphosulphonic acid salt of formula II,

The solvent used in the reaction can be selected from aliphatic ester solvents such as ethyl acetate, propyl acetate, butyl acetate and the like; Cj-C₆ alcoholic solvent such as methanol, ethanol,, n-propanol, isopropanol, n-butanol, isobutanol, ter-butanol and . the like; C₃-C₆ aliphatic ketonic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; C₂-C₄. aliphatic nitrile solvent such as acetonitrile, propionitrile and the like; of which alcoholic solvent and ester solvents are preferred. In most preferred embodiment ethanol and ethylacetate used.

The salt forming reaction cart be carried out 0 °C to reflux temperature of solvent employed. The reaction mass can be stirred from 1 to 24 hours, preferably till the completion of the reaction. Optionally, seeding can be carried out with camphosulphonic acid salt.

. In another aspect of invention, the compound obtained by following the above process can suitably be formulated to provide a pharmaceutical composition and which is further provided by the present invention a pharmaceutical composition comprising ivabradine or pharmaceutically acceptable salts thereof .

In another aspect of invention is to provide a novel, efficient, industrially advantageous one pot process for preparation of 3r(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula III by reacting 2-bromo-4,5-dimethoxybenzaldehyde of formula VII with cyano derivative, of formula VIII in the presence of a suitable base and a suitable solvent to form in- situ cyano-acrylic acid compound of formula IX. The cyano-acrylic acid compound of formula IX in-sit can be converted into 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula III.

In one embodiment cyano-acrylic acid compound of formula IX can be converted to 3-(2- bromo-4,5-dimethoxybenzene)propionitrile compound of formula III by reducing cyano- ■ acrylic acid compound of formula IX with a suitable reducing agent in the presence of a base to form cyano-propionic acid compound of formula X followed by decarboxylation.

The suitable reducing agent, used for reducing cyano-acrylic acid compound of formula IX, can be selected from sodium borohydride, lithium aluminium hydride; suitable base can be selected from alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and suitable solvent can be selected from water; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol or mixture thereof

In another embodiment, cyano-acrylic acid compound of formula IX can be converted to 3-(2- bromo-4,5-dimethoxybenzene)propionitrile compound of formula III by decarboxylating cyano-acrylic acid compound of formula IX with a suitable reducing agent in the presence of a base to form cinnamonitrile compound of formula XI followed by reduction. The base used during reaction of 2-bromo-4,5-dimethoxybenzaldehyde of formula VII with cyano derivative of formula VIII can be selected from inorganic base or organic bases. Inorganic base used in the reaction can be selected from an alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; an alkali metal carbonates selected from sodium carbonate, potassium carbonate, cesium carbonate and the like; an alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like, of which an alkali metal hydroxides is preferred, it is advantageous to carry out reaction in the presence of inorganic base, as reaction is very fast and goes to completion.

The solvent used in reaction can be selected from water; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ether solvents such as tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,2-dimethoxyethane, 1,2-diethoxyethane . and the like or mixture thereof.

The reaction can be carried out at temperature of 10°C to 60°C for 1 5 minutes to completion of reaction. Preferably the condensation reaction is carried out at 10°C to 50°C and it takes 15 minutes to 2 hours for completion to form cyano-acrylic acid compound of formula IX.

In one embodiment, when cyano-acrylic acid compound of formula IX is converted to compound of formula III by reducing cyano-acrylic acid compound of formula IX first followed by decarboxylation, the reduction reaction is preferably carried out at 10°C to 50°C and it takes about 2 hours for completion. After completion of reduction reaction, the reaction mass is cooled and quenched using an acid. Preferably, the reaction mass can be cooled to ambient temperature and pH can be adjusted to around 1-2 with hydrochloric acid. Thereafter, the reaction mixture is extracted using water immiscible solvents such as methylene dichloride, chloroform, carbon tetrachloride and the like, of which methylene dichloride is preferred. After layer separation, the solvent is distilled off to give 3-(2-bromo-4,5-dimefhoxy- phenyl)-2-cyano-propionic acid compound of formula X. 3-(2-Bromo-4,5-dimethoxy-phenyl)- 2-cyano-propionic acid of formula X, thus formed, can be optionally isolated from reaction mixture or can be used as such for further decarboxylation reaction.

Decarboxylation of cyano-propionic acid compound of formula X can be carried out in the presence of a suitable catalyst and a suitable solvent to form 3-(2-bromo-4,5-dimethoxy benzene)propionitrile of formula III. Catalyst used in the decarboxylation reaction . can be selected from tetrakis (triphenyl phosphine) palladium, palladium chloride, palladium acetate, palladium(II) trifluoroacetate, palladium oxides, salts of palladium such as palladium bromide, palladium fluoride, palladium iodide, palladium oxalate and the like. It is advantageous to carry out decarboxylation reaction in the presence of tetrakis (triphenyl phosphine) palladium catalyst as it improves in utility cost and operational efficiency of process on commercial scale. The solvent used in decarboxylation can be selected from water; aromatic hydrocarbon solvents such as benzene, toluene, xylene, 1,2-xylene, 1 ,4-xylene and the like, 1 ,2-dimethoxybenzene, . 1 ,2-diethoxy benzene; amide solvents such as dimefhylacetamide, diethylacetamide; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, nitrile solvents such as acetonitrile, propionitrile; alcoholic solvents such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane; and the like or mixture thereof.

The decarboxylation reaction can be carried out at ambient temperature to reflux temperature, optionally with seeding of pure 3-(2-bromo-4,5-dimethoxybenzene) propionitrile or preferably at a temperature of 30-170°C for 15 minutes to 6 hours to obtain 3-(2-bromo-4,5- dimethoxybenzene) propionitrile of formula III.

In another embodiment, where cyano-acrylic acid compound of formula IX is decarboxylated first followed by reduction, cyano-acrylic acid compound of formula IX can be decarboxylated in the presence of a suitable catalyst and a suitable solvent to form 2-bromo- 4,5-dimethoxycinnamonitrile compound of formula XI. Reducing in-situ cinnamonitrile compound of formula XI using a suitable reducing agent in the presence of a suitable base and a suitable solvent to obtain 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III. The suitable catalyst and a suitable solvent used for decarboxylation and a suitable reducing agent, base and solvents used for reduction are same as described above for the conversion of cyano-acrylic acid compound of formula IX into 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula I through cyano-propionic acid compound of formula X.

The resulting 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III can be crystallized from a suitable solvent. The suitable solvent can be selected from water; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol, acetonitrile, propionitrile, 1 ,4- dioxane, tetrahydrofuran and the like or mixture thereof. Optionally, crystallization can be facilitated by adding seeding of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula III. 3-(2-Bromo-4,5-dimethoxybenzene)propionitrile compound of formula III, prepared by present invention have purity in the range of 96 to 99.9% measured by HPLC and have assay in the range of 94-100% (w/w).

A one-pot synthesis is preferred to improve the efficiency of a chemical process, which involves multi steps, whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds would save time and resources while increasing chemical yield. Speed, diversity, efficiency and environmental amiability are some of the major advantages of these one pot multi steps reaction. They have emerged as valuable tools for the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds. <

The number of material handling steps is decreased. Consequently, the total processing time is snorter while maintaining a high yield and keeping production support to a minimum. At the same time, the number of required operators is also reduced.

However, due to the complexity of many pharmaceutical drug molecules, long multi-step syntheses aire required to construct the final compound. This in turn means use of large, amounts of solvent both for performing the reactions and for the isolation, purification of compounds at each stage of the synthesis and energy are required leading to a significant quantity of waste production at each stage of the synthesis. Furthermore, carrying out a one-pot process lowers any loss in yield resulting from the purification of intermediates. Overall, a one-pot procedure saves time, energy and the excessive usage of solvents and other chemicals, which ultimately leads to a reduction in waste production when compared to performing a stepwise synthesis. This has led to an increase in the research and development of pharmaceutical product and their intermediates, which combine multiple steps in. a one-pot process, for the synthesis of complex organic molecules. Therefore, one pot process has been employed for the preparation of 3-(2- bromo-4,5-dimethoxy benzene) propionitrile compound of formula I, precursor of 1 -cyano-4,5- dimethoxybenzoeyclobutane which is a key intermediate of ivabradine or pharmaceutically acceptable salt thereof.

The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC) ultrahigh pressure .liquid chromatography (UPLC), and the like.

In an alternate embodiment, present invention, provides a process for preparation of 3-(2- bromo-4,5-dimethoxy benzene)propionitrile compound of formula III with high yield and purity wherein any of intermediates, cyano-acrylic acid compound of formula IX or cyano propanoic acid compound of formula X or cinnamonitrile compound of formula XI or all can be isolated. ' ·

According to one another embodiment, the present invention provides a process for preparation of l -cyano-4,5-dimethoxybenzocyclobutane by employing highly pure 3-(2-bromo-4,5_.- dimethoxybenzene)propionitrile.

According to one another embodiment, the present invention provides a process for the preparation of ivabradine by employing highly pure 3-(2-bromo-4,5-dimethoxybenzene) propionitrile, by the methods reported in art or as provided in present invention.

The main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of ivabradine or pharmaceutically acceptable salt thereof by using highly pure 4,5-dimethoxy- l-cyano-benzocyclobutane derivatives. Further, present invention provides highly pure 4,5-dimethoxy-l-cyano-benzocyclobutane formula I, having assay greater than 95% w/w and having organic as well as inorganic impurities in minimum acceptable amount or free from such impurities. '

Further, the present invention provides a purification process of camphosulphonic acid salt of formula II by using a suitable solvent, which is cost-effective, nontoxic, easy to handle, and capable of removing chiral impurity to greater extend and results in improvement in yield. Furthermore, the present invention provides an industrially advantageous, economical and reproducible process for the preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile in high yield of greater, than 90% and high purity in the range of than 96-99.9% and the reaction time is also reduced by many folds as per process set out in present invention.

Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of compounds of the invention.

EXAMPLES:

Example 1: Purification of crude 4,5-dimethoxy-l-cyano-bcnzocyclobutanc

Crude 4,5-dimethoxy-l-cyano-benzocyclobutane' (l .OKg) was dissolved in toluene (7.QL) at 60-65°C. Silica gel (0.50Kg) and activated carbon (O. lO g) were successively added. The reaction mass was further stirred at 60-65 °C for 60 minutes. Thereafter the reaction mass was filtered through hyflo bed, the bed was washed with toluene (3.0L). Solvent was then distilled off completely under reduced pressure and hexane (1.50L) was slowly added to the reaction mass and then the reaction mass was refluxed for 30 minutes. The reaction mass was cooled to 0-5 °C and stirred at same temperature for 60 minutes. The resulting solid was filtered, washed with hexane (0.50L) and dried under vaccum at 60-65 °C for eight hours to obtain title compound as cream coloured powder, having purity 9,9.9% by HPLC and assay 99.3% w/w. Example 2: Preparation of 4,5-dimethoxy-l-(methyl amine)-benzocyclobutane

Pure 4,5-dimethoxy-l -cyano-benzocyclobutane (l OOg), methanol (800ml), sodium hydroxide (lO.Og) and Raney nickle (20.0g) were charged in the autoclave and stirred under 4.0-5.0 Kg./cm hydrogen pressure till reaction completion [4-5 hours]. The reaction mass was filtered through hyflo bed and the bed was washed with methanol (400ml). Solvent was distilled off completely under reduced pressure to get 4,5-dimethoxy- l -(methyl amine)-benzocyclobutane as an oily liquid. The oily residue was dissolved in methylene chloride (500ml) and washed with DM water (2x500ml). Solvent was distilled off completely at atmospheric pressure and filially the oily residue was degassed under reduced pressure.

Example 3: Preparation of boc protected 4,5-dimethoxy-l-(methylamine)-benzo cyclobutane

4,5-Dimefhoxy- l -(methyl amine)-benzocyclobutane (123g) was dissolved in methylene chloride (1.0L). Boc anhydride (132g) was added slowly. Reaction mass was stirred at ambient temperature till reaction completion [45 minutes]. DM water (500ml) was added and the reaction mass was stirred for further 5 minutes. The layers were separated and the organic layer was washed with DM water (500ml). The organic layer was dried over sodium sulphate and solvent was distilled off completely, n- Hexane (100ml) was added to the resulting residue and solvent was distilled off under . reduced pressure to obtain solid residue. Again n-hexane (400ml) was added and the reaction mass was refluxed under stirring for 15 minutes. The reaction mass was cooled to 10-20 °C and stirred for 60 minutes. The solid was filtered, washed with n-hexane (100 ml) and finally dried at 50-60 °C to . obtain boc protected 4,5- dimethoxy-l -(methyl amine)-benzocyclobutane as a creamish to off white solid having purity 99.55% by HPLC.

Example 4: preparation of (R,S)-N-[(4,5-dimethoxybenzocycIobut-l-yl)-methyl]-N- (methyl) amine

Boc-protected 4,5-dimethoxy-l -(methyl amine)-benzocyclobutane (132g) was dissolved in tetrahydrofuran (0.39L). In a separate RBF, lithium aluminium hydride (34. Og) was taken in tetrahydrofuran (500ml) under inert atmosphere and was heated to reflux temperature. The solution of boc protected 4,5-dimethoxy- l -(methyl amine)-benzocyclobutane, prepared above, was added slowly to the reaction mass and then the reaction mass was further refluxed for 2 hours. After completion of reaction, the reaction mass was cooled to 0 °C. DM water (139ml) was added slowly at 0-15 °C followed by addition of 20% aqueous sodium hydroxide solution (25g). The reaction mass was further stirred at 10-25 °C for 15 minutes. The reaction mass was filtered through hyflo bed and the bed was washed with tetrahydrofuran (1.0L). Solvent was distilled off completely under reduced pressure. Methylene chloride (1.0L) was added and distilled off completely to obtain the title compound.

Example 5: Preparation of (R,S)-N-[(4,5-dimcthoxybcnzocyclobut-l-yl)-methyrj-N- (methyl) amine

A solution of boc-protected 4,5-dimethoxy-l -(methyl amine)-benzocyclobutane (200g) in toluene (1.0L) was added slowly to a vitride solution (650 ml, approx 70% in toluene) in toluene (1.0L) ,at 75°C and maintained the temperature of the reaction mass between 75-90 °C. After completion of addition, the reaction mass was stirred at 80-90°C. After reaction completion, the reaction mass was cooled to 0-5°C. Dilute aqueous sodium hydroxide solution (8.0g in 1.0L) was added slowly at 0-20°C to the resulting reaction mass and then the reaction mass was stirred at room temperature for 15 minutes and filtered through hyflo bed. The layers were separated and the aqueous layer was further extracted with toluene (200ml). The combined organic layer was washed ith 10% aqueous sodium chloride solution (1.0L). The organic layer was concentrated under reduced pressure, and methylene chloride (400ml) was added to the resulting residue and then solvent was distilled off. Ethanol (200ml) was added to the resulting compound and then distilled off under reduced pressure to obtain title compound, having purity 98.73% by HPLC and yield 100%.

Example 6: Preparation of crude (S)-N-[(4,5-dimethoxybenzocycIobut-l-yl)-methylj-iV- (methyl)amine camphosulphonic acid salt

To a solution of 4,5-dimethoxybenzocyclobut- l-yl-methyl-N-methylamine (88g) in ethanol (300ml), D-(+) camphorsulphonic acid (1 12g) was added and the reaction mass was stirred at reflux temperature for 45 minutes. Solvent was distilled off under reduced pressure, Ethyl acetate (200ml) and seed of pure methyl amine CSA salt (0.50g) were added and the solvent was distilled off completely under reduced pressure to obtain a residue. Ethyl acetate (500ml) was added and the reaction mass was stirred at reflux temperature for 15 minutes to obtain a suspension. The reaction mass was cooled to 0-5 °C and stirred for 60 minutes. The solid was filtered and washed with ethyl acetate (200ml) and dried at 55-65 °C under vaccum to obtain title compound as a white to off white solid, having chiral purity 61.70% by HPLC. Example 7: Purification of crude (S)-N-[(4,5-dimcthoxybcnzocydobut-l-yl)-mcthyl]-N- (methyl)aniine camphosulphonic acid salt

A suspension of crude (S)-N-[(4,5-dimethoxybenzocyclobut- l -yl)-methyl]-N-(rnethyl)arnine camphosulphonic acid salt (H Og) in methanol ( 1 10ml) was heated to reflux temperature till complete dissolution. Thereafter, tertiary butyl methyl ether (880ml) was added slowly to the clear reaction mass and further refluxed for 15 minutes. The reaction mass was cooled to 35 °C and stirred for 30-40 minutes. The resulting solid was filtered, washed with a mixture of MTBE and methanol and dried to obtain title compound having chiral purity 98.54% and yield of 69%. Example 8: Preparation of 3-(2-bromo-4,5-dimcthoxybcnzciic)propionitrile

To a suspension of 2-bromo-4,5-dimethoxybenzaldehyde (50. Og) in ethanol at 25-30°C, a solution of sodium hydroxide ( I6.30g) in water (32ml) was added and the reaction mass was stirred for 15 minutes. Ethylcyanoacetate (27.7g) was added and the reaction mass further stirred at 30-40°C for 60 minutes, After completion of the reaction (monitored by HPLC), the reaction mixture comprising of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid was carried forward to the next step without isolation.

A solution of sodium bicarbonate (94g) in water (IL) was added to reaction mixture of 3-(2- bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid and stirred for 15 minutes. A solution of sodium borohydride (15.4g) in aqueous sodium hydroxide (7.40g sodium hydroxide in 34 ml water) was added dropwise to the previous reaction mass at 25-35 °C and then the reaction mass was stirred at 25-35°C for 30 minutes. Thereafter, the reaction mass was heated to 40°C, stirred for 30 minutes. Thereafter, the reaction mass was cooled to 20-30°,C and pH was adjusted to around 1 -2 with concentrated hydrochloric acid (200ml). The reaction mass was extracted with methylene chloride (2x 250ml). Solvent was distilled off to obtain 3-(2-bromo- 4,5-dimethoxy-phenyl)-2-cyano-propionic acid and it was carried forward to the next step without isolation. The resulting crude product was taken in toluene and heated to azeotropic refluxing with stirred till water or low boiling solvents were removed. Tetrakis (triphenylphosphine) palladium (200mg) was added and reaction mass was . refluxed at 1 10- 1 15°C for 4-5 hours. After reaction completion, the reaction mass was cooled to 25-30°C, filtered through hyflo bed, the bed was washed with toluene (200ml) and toluene was distilled off under reduced pressure. The resulting residue was dissolved in methanol (100ml) and the reaction mass was cooled to 20-25°C. Water (250ml) was added drop wise to the. reaction mass, followed by addition of seeds of 3-(2-bromo-4,5-dirnethoxybenzene) propionitrile. The reaction mass was cooled to 0- 10°C and was further stirred for one hour. The resulting solid was filtered, washed with DM water (250ml) and dried in oven at 50-60 °C under vaccum for 6 hours to get 52g (9,4%) of title compound as yellowish solid, having purity 97.59% measured by HPLC.

Example 9 : Preparation of 3-(2-bromo-4,5-dimethoxybcnzcnc)propionitriIc

To a suspension of 2-bromo-4,5-dimethoxybenzaldehyde (I50.0g) in ethanol (1500ml) at 25- 30°C a solution of sodium hydroxide (48.9g) in water (100 ml) was added and the reaction mass was stirred for 15 minutes. Ethylcyanoacetate (84.1 g) was added and the reaction mass was . further stirred at 30-40°C for 60 minutes. After completion of reaction (monitored by HPLC) the reaction mixture comprising of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano^:acrylic acid was carried forward to the next step without isolation.

A solution of sodium bicarbonate (282. Og) in water (2.8L) was added to the reaction mixture of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid and stirred for 15 minutes. A solution of sodium borohydride (46.2g) in aqueous sodium hydroxide (24.4g of sodium hydroxide in 102 ml water) was added drop wise to the reaction mass at 25-35 °C and then the obtained reaction mass was stirred at 25-35°C for 30 minutes. Thereafter, the reaction mass was heated to 40 °C and stirred for 30 minutes. Then, the reaction mass was cooled to 20-30°C and pH was adjusted to around 1-2 with concentrated hydrochloric acid (700ml). The reaction mass was extracted with methylene chloride (2 x 750ml). Solvent was distilled off to obtain 3-(2-bromo- 4,5-dimethoxy-phenyl)-2-cyano-propionoic acid and it was carried forward to the next step without isolation. To the resulting residue N,N- dimethyl acetamide (390ml) was added to obtain a reaction mixture, heated the reaction mixture under stirring to 145-160°C for 1 hour . After reaction completion (monitored by HPLC), the reaction mass was cooled to 40-50°C. Water (900ml ) was added dropwise, followed by addition of seeds of 3-(2-bromo-4,5- dimefth0xybenzene)propionitrile. The reaction mass was further stirred at 40-50°C for 60 minutes and then the reaction mass was cooled to 20-30 °C and was stirred for 60 minutes . The resulting solid was filtered, washed with water (300ml ) and suck dried for 15 minutes and finally dried at 60-65 °C to get 149 g of 3-(2-bromo-4,5-dimetthoxy benzene)propionitrile having purity 97.39% measured by HPLC and assay 100. l w/w.

Example 10: Preparation of 3,4-dimethoxy-bicyclo[4.2.0]octa-l(6),2,4-triene-7- carbonitrilc (or 4,5-dimcthoxy-l-cyano-benzocyclobutane)

n-Butyl lithium solution (40 ml) in hexane was added slowly to a mixture of tetrahydrofuran

(50 ml) and N,JV-diisopropylamine (16 ml ) at -20 to - 10 °C and reaction mass was further maintained at -20 to -10°C for 15 minutes under inert atmosphere. A solution of 3-(2-bromo- 4,5-dimethoxy benzene)propionitrile (10 g) in toluene (50 ml) was added slowly at -20 to - 10°C to above reaction mass and then further stirred under nitrogen atmosphere at -20 to - 10°C for 60 minutes. After reaction completion, hydrochloric acid solution (IN, 100 ml) was added slowly to the reaction mass. The temperature of the reaction mass was raised to 20-30°C, stirred for 30 minutes and layers were separated.

To the organic layer, hydrochloric acid solution (IN, 100ml) Was added and stirred for 30 minutes and layers were separated and the combined organic layer was washed with demineralized water (50ml). To the organic layer, activated charcoal (1.0 g), silica gel (2.0 g) were added and the reaction mass was stirred at 50-60°C for 30 minutes. The reaction mass was filtered, washed with toluene (30ml). Solvent was distilled off completely under reduced pressure. Ethanol (20 ml) was added to the resulting residue and the reaction mass was cooled to 20-30°C and seeds of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile (l .Og) was added and stirred for further 60 minutes. The reaction mass was further cooled to 0 to 5°C and stirred at same temperature for 60 minutes. The resulting solid was filtered, washed with cooled ethanol (5 ml ) and dried at 50-60°C to obtain 6.0g of pure 3,4-dimethoxy-bicyclo[4.2.0jocta-l(6),2,4- triene-7-carbonitrile having purity 99.72% measured by HPLC and having assay 97.8%. ·

Claims

WE CLAIM:

1. A process of purification of 4,5-dimethoxy-l -cyano-benzocyclobutane of formula I,

Formula I

a) providing a solution of crude cyano intermediate of formula I, in an aromatic hydrocarbon solvent;

b) adding silica gel and / or activated carbon to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) filtering the reaction mass;

e) distilling off the solvent;

f) adding an aliphatic hydrocarbon solvent to the resulting reaction mass; < g) heating the reaction mass at reflux temperature;

h) cooling the resulting mixture; and

i) isolating pure 4,5-dimethoxy-l -cyano-benzocyclobutane of formula I.

2. The, process according to claim 1 , wherein in step a) aromatic hydrocarbon solvent is benzene, toluene, xylene or mixture thereof; in step 1) aliphatic hydrocarbon solvent is hexane, heptane, cyclohexane or mixture thereof.

3. A process for purification of (S)-N-[(4,5-dimethoxybenzocyclobut- l-yl)-methyl]-A^r-(methyl) amine camphosulphonic acid salt of formula II,

Formula II

b) adding an ether as anti solvent slowly to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) , cooling the resulting mixture; and

e) isolating pure camphosulphonic acid salt of formula II.

4. The process according to claim 3, wherein in step a) alcoholic solvent includes C i -C₆ alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ter-butanol and the like or mixture thereof; in step b) antisolvent includes ether solvent such as diethyl ether, isopropyl ether, tertiarybutyl methyl ether, tetrahydrofuran, dioxane; Cr Cio cyclic or acyclic saturated hydrocarbon solvent such as hexane, heptane, cyclohexane or mixture thereof.

5. A process for preparation of (R,S)-N-[(4,5-dimethoxybenzocyclobut-l -yl)-methyl]-A - (methyl) amine of formula VI,

Formula VI

comprising the steps of:

a) protecting the intermediate of formula IV

Formula IV

with boc anhydride in the presence of a suitable solvent to form intermediate of formula V; Formula V

b) reducing boc-protected intermediate in a suitable reducing agent and a suitable solvent to get intermediate of formula VI.

6. The process according to claim 5, wherein in step a) solvent is selected from halogenated solvents such as methylene dichloride, chloroform, carbon tetrachloride and the like; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,2-dimethyl ether, 1 ,2-diethyl ether, diisopropyl ether, tertiary butyl methyl ether and the like or mixture thereof; in step b) reducing agent includes hydride such as lithium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride; vitride and the like; in step b) solvent is selected from the group comprising ether solvents such as diethyl ether, propyl ether, butyl ether, tetrahydrofuran, dioxane, 2-methyl tetrahydrofuran, 1 ,2-dimethylether, 1 ,2- diethylether and the like; aromatic hydrocarbon solvents such as benzene, xylene, toluene and the like or mixture thereof.

7. A process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III, Formula III

Formula VII with alkyl cyano derivative of formula VIII,

Formula VIII

wherein R is selected from -COOR' and R' is H, or an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or ter -butyl or alike,

in the presence of a base in a solvent at suitable temperature to form cyano-acrylic acid compound of formula IX,

Formula IX

b) converting cyano-acrylic acid compound of formula IX to 3-(2-bromo-4,5- dimethoxybenzene) propionitrile of formula III.

c) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III with a suitable solvent.

The process as claimed in claim 7, wherein in step a) base is organic base or inorganic base selected from an alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; an' alkali metal carbonates is selected from sodium carbonate, potassium carbonate, cesium carbonate; an alkali metal bicarbonates is selected from sodium bicarbonate, potassium bicarbonate, cesium v bicarbonate; in step a) solvent is selected from water; alcohols selected from methanol, ethanol, propanol, isopropanol, tert- butanol; halogenated solvents selected from dichloromethane, 1,2-dichloroethane, chloroform; ether solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,2- dimethoxyethane, 1 ,2-diethoxyethane or mixture thereof.

The process as claimed in claim 7, wherein in step b) conversion of cyano-acrylic acid compound of formula IX to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III is achieved by comprising the steps of : i) reducing in-situ cyano-acrylic acid compound of formula IX using a suitable reducing agent in the presence of a suitable base and a suitable solvent to obtain cyano-propionic acid compound of formula X,

Formula X

ii) decarboxylating in-situ the resulting cyano-propionic acid compound of formula X, in the^" presence of a suitable catalyst in a suitable solvent at suitable temperature to form 3-(2- bromo-4,5-dimethoxybenzene)propionitrile of formula III.

0. The process as claimed in claim 9, wherein in step i) reducing agent is selected from sodium borohydride, lithium aluminium hydride; suitable base selected from alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate; suitable solvent selected from water; alcohols selected from methanol, ethanol, propanol,.. isopropanol, tert-butanol. or mixture thereof; in step ii) suitable catalyst used for decarboxylation is selected from tetrakis (triphenylphosphine)p'alladiurn, palladium chloride, palladium acetate, palladium(II) trifluoroacetate, palladium oxides, salts of palladium such as palladium bromide, palladium fluoride, palladium iodide,_, palladium oxalate; in step ii) suitable solvent is selected from water; aromatic hydrocarbon solvents selected from benzene, toluene, xylene, 1 ,2-xylene, 1 ,4-xylene; 1 ,2-dimethoxybenzene, 1 ,2- diethoxy benzene; amide solvents selected from dimethylacetamide, diethylacetamide; ether solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, niirile solvents selected from acetonitrile, propionitrile; alcoholic solvents is selected from methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents selected from dichloromethane, 1 ,2-dichloroethane or mixture thereof. ¹

1. The process as claimed in claim 7, wherein in step b) conversion of cyano-acrylic acid compound of formula IX to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I is achieved by comprising the steps of :

i) decarboxylating in-situ the resulting cyano-acrylic acid compound of formula IX in the catalyst and a suitable solvent to form 2-bromo-4,5- ompound of formula XI,

Formula XI

ii) reducing in-siiu cinnamonitrile compound of formula XI using a suitable reducing agent in the presence of a suitable base and a suitable solvent to obtain 3-(2-bromo-4,5- dimethoxybenzene)propionitrile of formula III.

12. The process as claimed in claim 1 1, wherein in step i) a suitable catalyst used for decarboxylation is selected from tetrakis (triphenylphosphine)palladium, palladium chloride, palladium acetate, palladium(II) trifluproacetate, palladium oxides, salts of palladium such as palladium bromide, palladium fluoride, palladium iodide, palladium oxalate; step i) suitable solvent is selected from water; aromatic hydrocarbon solvents selected from benzene, toluene, xylene, 1 ,2-Xylene, 1 ,4-xylene; 1 ,2-dimethoxybenzene, 1 ,2-diethoxy benzene; amide solvents selected from dimethylacetamide, diethylacetamide; ether solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, nitrile solvents selected from acetonitrile, propionitrile; alcoholic solvents such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents selected from dichloromethane, ,2-dichloroethane or mixture thereof; in step ii) reducing agent is selected from sodium borohydride, lithium aluminium hydride; suitable base selected from alkali metal bicarbohates such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate; suitable solvent selected from water; alcohols selected from methanol, ethanol, propanol, isopropanol, tert-butanol or mixture thereof.

13. The process as claimed in claim 7, wherein in step c) a suitable solvent for crystallization is selected from water; alcohols selected from methanol, ethanol, propanol, isopropanol, tert- butanol, acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran or mixture thereof.

14. A process for the preparation o f ivabradine or pharmaceutically acceptable salt thereof, com -benzocyclobutane of formula I, prepared

Formula I

as claimed in claim 1 and converting it to ivabradine or pharmaceutically acceptable salt thereof.

15. A process for the preparation of ivabradine or pharmaceutically acceptable salt thereof, comprises the steps of :

a) providing a solution of crude camphosulphonic acid salt of formula II in an alcoholic solvent; Formula II

b) adding an ether as antisolvent slowly to the reaction mass;

c) stirring the reaction mixture at heating temperature for 0-2 hours;

d) cooling the resulting mixture;

e) isolating pure camphosulphonic acid salt of formula II and,

f) converting pure camphosulphonic acid salt of formula II obtained in step e) to ivabradine or pharmaceutically acceptable salt thereof

16. A process for the preparation of ivabradine or pharmaceutically acceptable salt thereof, comprises using (R,S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl) amine of formula VI prepared as claimed in claim 5 and ,

Formula VI

converting it to ivabradine or pharmaceutically acceptable salt thereof.

17. A process for the preparation of ivabradine or pharmaceutically acceptable salt thereof, comprises the steps of :

a) reacting 2-bromo-4,5-dimethoxybenzaldehyde of formula VII,

Formula VII with alkyl cyano derivative of formula VIII,

>^R Formula VIII wherein R is selected from -COOR' and R' is H, or an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or ter-butyl or alike,

in the presence of a base in a solvent at suitable temperature to form cyano-acrylic acid compound of formula IX, Formula IX

b) converting cyano-acrylic acid compound of formula IX to 3-(2-bromo-4,5- dimethoxybenzene) propionitrile of formula III,

c) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III with a suitable solvent,

d) converting 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula III to ivabradine or pharmaceutically acceptable salt thereof.

18. The process as claimed in claim 17, wherein in step a) base is organic base or inorganic base selected from an alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; an alkali metal carbonates selected from sodium carbonate, potassium carbonate, cesium carbonate; an alkali metal bicarbonates selected from sodium bicarbonate, potassium bicarbonate, cesium bicarbonate; in step a) solvent is selected from, water; alcohols selected from methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents selected from dichloromethane, 1 ,2-dichloroethane, chloroform; ether solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,2-dimethoxyefhane, 1,2- diethoxyethane or, mixture thereof.

19. The process as claimed in claim 17, wherein in step b) conversion of cyano-acrylic acid compound of formula IX to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula III is carried out by process as claimed in claims 9 and 1 1 .

20. The process as claimed in claim 17, wherein in step c) suitable solvent for crystallization is selected from water; alcohols selected from methanol, ethanol, propanol, isopropanol, tert- butanol, acetonitrile, propionitrile, 1 ,4-dioxane, tetrahydrofuran or mixture thereof.