DESC:FORM 2
THE PATENTS ACT, 1970
[39 of 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

PROCESS FOR THE PREPARATION OF
3-(2-BROMO-4,5-DIMETHOXYBENZENE)PROPIONITRILE

IND-SWIFT LABORATORIES LIMITED,
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following specification particularly describes the invention and the manner in which is to be performed.

FIELD OF THE INVENTION
The present invention relates to an efficient and industrially advantageous process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I, with high purity and high yield,

Formula I

wherein compound of formula I is an important precursor of 1-cyano-4,5-dimethoxybenzocyclobutane, a key intermediate in the preparation of ivabradine.

BACKGROUND OF THE INVENTION
Ivabradine and its pharmaceutically acceptable salts have very valuable pharmacological and therapeutic properties and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxy benzocyclo but-1-yl)methyl-N-(methyl) amino) propyl) -1,3,4,5-tetrahydro-2H-3-benzazepine-2-one and is represented by following structure.

Formula III

Ivabradine is useful in many cardiovascular diseases such as angina pectoris, myocardial infarction and associated rhythm disturbances.
Ivabradine and its pharmaceutically acceptable salts were first disclosed in US patent 5,296,482. The patent also discloses a process for the preparation of ivabradine and its pharmaceutically acceptable salts through 4,5-dimethoxy-1-cyano-benzocyclobutane intermediate and which in turn can be prepared from 3-(2-bromo-4,5-dimethoxy- benzene)propionitrile. The processes of preparation of 4,5-dimethoxy-1-cyano-benzo cyclobutane intermediate and its precursor 3-(2-bromo-4,5-dimethoxybenzene) 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 and 4,5-dimethoxy-1-cyano benzo cyclobutane have been disclosed and are discussed herein.

An article, namely Tetrahedron 1973 (29), pp. 73-76 discloses a process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile, as shown in below scheme,

wherein 2-bromo-4,5-dimethoxybenzaldehyde was reacted with cyanoacetic acid in the presence of ammonium acetate, benzene, pyridine and the reaction mixture was heated under reflux to form pyridine salt of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid. In a solution of pyridine salt of resulting intermediate saturated sodium bicarbonate and sodium borohydride were added and then the reaction mixture was acidified with hydrochloric acid (10%) to yield 3-(2-bromo-4,5-dimethoxyphenyl)-cyanopropionic acid. The resulting intermediate was recrystallized from benzene-dimethylformamide and the crystallized product then undergoes facile decarboxylation with dimethylacetamide or hexamethyltriamide phosphate at 170 ºC and isolating 3-(2-bromo-4,5-dimethoxybenzene)propionitrile from the reaction mixture. Finally, the resulting product was recrystallized from ethanol.
It has been observed that the said process suffers from several drawbacks, such as the use of pyridine, which is toxic in nature, for preparing pyridine salt of 3-(2-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid and eventually adding to the cost of the process, and hence utility cost was not achieved. The disclosure is also silent about the purity of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile and results in over all yield of 59-65 % from 2-bromo-4,5-dimethoxy benzaldehyde.

Another article, namely Journal of Chemical Research 2009, pp. 420-422 discloses a process for preparation of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile, via two routes, of which one route similar is that reported in Tetrahedron 1973 (29) pp. 73-76 with some minor changes and gives 2-bromo-4,5-dimethoxyphenylpropionitrile having 96.5% purity in overall yield of 37%. The said process is not attractive from commercial point of view, being very low yielding and also makes use of pyridine, which is toxic in nature.
Other alternate route reported is as shown below in the scheme.

The process comprises condensation of 2-bromo-4,5-dimethoxybenzaldehyde with acetonitrile in the presence of sodium hydroxide to give 2-bromo-4,5-dimethoxycinnamonitrile 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. The above process also suffers from several drawbacks like use of pyridine, which is toxic in nature and have very bad odour, 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.

Another article, namely J. Org. Chem. 1972 (37), pp. 3374-3376 discloses a process for the preparation of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile, as shown below in the scheme.


The process comprises reduction of 3,4-dimethoxycinnamonitrile using palladium on carbon (5%) in tetrahydrofuran under hydrogen gas pressure for 48 hours to get 3,4-dimethoxyphenylpropionitrile. The resulting compound was brominated using bromine solution in acetic acid at 18ºC. After work up, crude 2-bromo-4,5-dimethoxyphenylpropionitrile was isolated and recrystallized twice from methanol and water to obtain pure 2-bromo-4,5-dimethoxyphenylpropionitrile 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.

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 1-cyano-4,5-dimethoxybenzocyclobutane, which in turn is a key intermediate in the preparation of ivabradine. Therefore, the present invention fulfills the need in the art and provides an cost effective, less time consuming, industrially viable process for the preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile in high purity and high yield.

OBJECT OF THE INVENTION
The main 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 1-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 the preparation of 1-cyano-4,5-dimethoxybenzocyclobutane by employing highly pure 3-(2-bromo-4,5-dimethoxybenzene)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 novel, convenient, industrially advantageous and efficient process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I,

Formula I

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

Formula II

with alkyl cyano derivative of formula III,

Formula III

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 IV,

Formula IV

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

Formula V

c) decarboxylating in-situ the resulting cyano-propionic acid compound of formula V, in the presence of a suitable catalyst and a suitable solvent to form 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I.
d) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I with a suitable solvent.
wherein corresponding cyano compounds of formulae IV and V are not isolated.

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

Formula II

with alkyl cyano derivative of formula III,

Formula III

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 IV,

Formula IV

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

Formula VI

c) reducing in-situ cinnamonitrile compound of formula VI 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 I.
d) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I with a suitable solvent.
wherein corresponding cyano compounds of formulae IV and VI are not isolated.

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

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

According to one another embodiment, 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 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.

According to one more embodiment, 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 IV or cyano propanoic acid compound of formula V or cinnamonitrile compound of formula VI 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 novel, efficient, industrially advantageous one pot process for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula I by reacting 2-bromo-4,5-dimethoxybenzaldehyde of formula II with cyano derivative of formula III in the presence of a suitable base and a suitable solvent to form in-situ cyano-acrylic acid compound of formula IV. The cyano-acrylic acid compound of formula IV in-situ can be converted into 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula I.
In one embodiment cyano-acrylic acid compound of formula IV can be converted to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula I by reducing cyano-acrylic acid compound of formula IV with a suitable reducing agent in the presence of a base to form cyano-propionic acid compound of formula V followed by decarboxylation.
The suitable reducing agent, used for reducing cyano-acrylic acid compound of formula IV, 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 IV can be converted to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile compound of formula I by decarboxylating cyano-acrylic acid compound of formula IV with a suitable reducing agent in the presence of a base to form cinnamonitrile compound of formula VI followed by reduction.
The base used during reaction of 2-bromo-4,5-dimethoxybenzaldehyde of formula II with cyano derivative of formula III 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 10oC to 60oC for 15 minutes to completion of reaction. Preferably the condensation reaction is carried out at 10oC to 50oC and it takes 15 minutes to 2 hours for completion to form cyano-acrylic acid compound of formula IV.
In one embodiment, when cyano-acrylic acid compound of formula IV is converted to compound of formula I by reducing cyano-acrylic acid compound of formula IV first followed by decarboxylation, the reduction reaction is preferably carried out at 10oC to 50oC 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-dimethoxy-phenyl)-2-cyano-propionic acid compound of formula V. 3-(2-Bromo-4,5-dimethoxy-phenyl)-2-cyano-propionic acid of formula V, 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 V can be carried out in the presence of a suitable catalyst and a suitable solvent to form 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I. 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 the decarboxylation reaction in the presence of tetrakis (triphenyl phosphine) palladium catalyst as it improves in utility cost and operational efficiency of the 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 dimethylacetamide, 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 30-170ºC for 15 minutes to 6 hours to obtain 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I.
In another embodiment, where cyano-acrylic acid compound of formula IV is decarboxylated first followed by reduction, cyano-acrylic acid compound of formula IV can be decarboxylated in the presence of a suitable catalyst and a suitable solvent to form 2-bromo-4,5-dimethoxycinnamonitrile compound of formula VI. Reducing in-situ cinnamonitrile compound of formula VI 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 I.
The suitable catalyst and a suitable solvent used for decarboxylation and suitable reducing agent, base and solvents used for reduction are same as described above for the conversion of cyano-acrylic acid compound of formula IV into 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I through cyano-propionic acid compound of formula V.
The resulting 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I 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 I.
3-(2-Bromo-4,5-dimethoxybenzene)propionitrile compound of formula I, 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 shorter 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 are 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-dimethoxybenzocyclobutane 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) ultra-high 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 I with high yield and purity wherein any of intermediates, cyano-acrylic acid compound of formula IV or cyano propanoic acid compound of formula V or cinnamonitrile compound of formula VI or all can be isolated.
According to one another embodiment, 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 one another embodiment, the present invention provides a process for the preparation of ivabradine or pharmaceutically acceptable salt thereof by employing highly pure 3-(2-bromo-4,5-dimethoxybenzene)propionitrile, by the methods reported in art or as provided in present invention. Generally process for the preparation of ivabradine or pharmaceutically acceptable salt thereof comprises the cyclization of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile to give 1-cyano-4,5-dimethoxybenzocyclobutane, followed by reduction of 1-cyano-4,5-dimethoxybenzocyclobutane to provide N-[( 4,5-dimethoxybenzocyclobut-1-yl]-methylamine or salt thereof. The resulting methylamine compound can be converted to methylated methylamine derivative through corresponding carbamate intermediate which can under go reduction to form N-[( 4,5-dimethoxybenzocyclobut-1-yl]-methyl)-N-(methyl)amine or salt thereof. The racemic intermediate may be then resolved using a suitable resolving agent which includes but not limited to (d)-camphosulphonic acid to produce the desired isomer, namely (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl) amine , which can be then condensed with 7,8-dimethoxy-3-[3-iodopropyl]-1,3-dihydro-2H-3-benzazepin-2-one, in the presence of a base to give corresponding benzazepine derivative, (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclo but-l-yl)methyl]-N-(methyl)amino)propyl)-1,3-dihydro-2H-3-benzazepin-2-one. The resulting benzazepine derivative can be then reduced with a suitable hydrogenating agent to produce ivabradine, which can optionally be purified by using suitable technique and finally converting ivabradine into a suitable pharmaceutically acceptable salt thereof.
The main advantage of the present invention is that it provide 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.
It is against this and other backgrounds, which shall be filed in a detailed manner in complete specifications, in due course, the present invention is brought out and explained in following non limiting examples.

EXAMPLES:
Example 1: Preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile
To a suspension of 2-bromo-4,5-dimethoxybenzaldehyde (50.0g) in ethanol at 25-30oC, a solution of sodium hydroxide (16.30g) 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 30-40oC 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 (1L) 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 oC and then the reaction mass was stirred at 25-35oC for 30 minutes. Thereafter, the reaction mass was heated to 40oC, stirred for 30 minutes. Thereafter, the reaction mass was cooled to 20-30oC 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 110-115oC for 4-5 hours. After reaction completion, the reaction mass was cooled to 25-30ºC, 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 20-25oC. Water (250ml) was added drop wise to the reaction mass, followed by addition of seeds of 3-(2-bromo-4,5-dimethoxybenzene) propionitrile. The reaction mass was cooled to 0-10oC and was further stirred for one hour. The resulting solid was filtered, washed with DM water (250ml) and dried in oven at 50-60 oC under vaccum for 6 hours to get 52g (94%) of title compound as yellowish solid, having purity 97.59% measured by HPLC.
Example 2 : Preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile
To a suspension of 2-bromo-4,5-dimethoxybenzaldehyde (150.0g) in ethanol (1500ml) at 25-30oC a solution of sodium hydroxide (48.9g) in water (100 ml) was added and the reaction mass was stirred for 15 minutes. Ethylcyanoacetate (84.1g) was added and the reaction mass was further stirred at 30-40oC 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 (282.0g) 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 oC and then the obtained reaction mass was stirred at 25-35oC for 30 minutes. Thereafter, the reaction mass was heated to 40 oC and stirred for 30 minutes. Then, the reaction mass was cooled to 20-30oC 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 145-160oC for 1 hour . After reaction completion (monitored by HPLC), the reaction mass was cooled to 40-50oC. Water (900ml ) was added dropwise, followed by addition of seeds of 3-(2-bromo-4,5-dimetthoxybenzene)propionitrile. The reaction mass was further stirred at 40-50oC for 60 minutes and then the reaction mass was cooled to 20-30 oC 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 oC to get 149 g of 3-(2-bromo-4,5-dimetthoxybenzene)propionitrile having purity 97.39% measured by HPLC and assay100.1w/w.
Example 3: Preparation of 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile (or 4,5-dimethoxy-1-cyano-benzocyclobutane)
n-Butyl lithium solution (40 ml) in hexane was added slowly to a mixture of tetrahydrofuran (50 ml) and N,N-diisopropylamine (16 ml ) at -20 to -10 oC and reaction mass was further maintained at -20 to -10oC for 15 minutes under inert atmosphere. A solution of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile (10 g) in toluene (50 ml) was added slowly at -20 to -10oC to above reaction mass and then further stirred under nitrogen atmosphere at -20 to -10oC for 60 minutes. After reaction completion, hydrochloric acid solution (1N, 100 ml) was added slowly to the reaction mass. The temperature of the reaction mass was raised to 20-30oC, stirred for 30 minutes and layers were separated.
To the organic layer, hydrochloric acid solution (1N, 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 50-60oC 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 20-30oC and seeds of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile (1.0g) was added and stirred for further 60 minutes. The reaction mass was further cooled to 0 to 5oC and stirred at same temperature for 60 minutes. The resulting solid was filtered, washed with cooled ethanol (5 ml ) and dried at 50-60oC to obtain 6.0g of pure 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile having purity 99.72% measured by HPLC and having assay 97.8%.

,CLAIMS:WE CLAIM:
1. A rocess for preparation of 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I,

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

Formula II

with alkyl cyano derivative of formula III,

Formula III
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 IV,


Formula IV

b) converting cyano-acrylic acid compound of formula IV to 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula I, and
c) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I with a suitable solvent.

2. The process as claimed in claim 1, 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 bicarbonate; wherein 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.
3. The process as claimed in claim 1, wherein in step b) conversion of cyano-acrylic acid compound of formula IV to 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I is achieved by comprising the steps of :
i) reducing in-situ cyano-acrylic acid compound of formula IV using a suitable reducing agent in the presence of a suitable base and a suitable solvent to obtain cyano-propionic acid compound of formula V,

Formula V

ii) decarboxylating in-situ the resulting cyano-propionic acid compound of formula V, 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 I.

4. The process as claimed in claim 3, 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)palladium, palladium chloride, palladium acetate, palladium(II) trifluoroacetate, palladium oxides, salts of palladium such as palladium bromide, palladium fluoride, palladium iodide, palladium oxalate; wherein 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, nitrile 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.

5. The process as claimed in claim 1, wherein in step b) conversion of cyano-acrylic acid compound of formula IV to 3-(2-bromo-4,5-dimethoxy benzene)propionitrile of formula I is achieved by comprising the steps of :
i) decarboxylating in-situ the resulting cyano-acrylic acid compound of formula IV in the presence of a suitable catalyst and a suitable solvent to form 2-bromo-4,5-dimethoxycinnamonitrile compound of formula VI,

Formula VI
ii) reducing in-situ cinnamonitrile compound of formula VI 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 I.
6. The process as claimed in claim 5, wherein in step i) a suitable catalyst used for decarboxylation is selected from tetrakis (triphenylphosphine)palladium, palladium chloride, palladium acetate, palladium(II) trifluoroacetate, 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 solvent selected from benzene, toluene, xylene, 1,2-xylene, 1,4-xylene; 1,2-dimethoxybenzene, 1,2-diethoxy benzene; amide solvent selected from dimethylacetamide, diethylacetamide; ether solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, nitrile solvents selected from acetonitrile, propionitrile; alcoholic solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents selected from dichloromethane, 1,2-dichloroethane or mixture thereof; in step ii) 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; and alcohol.

7. The process as claimed in claim 1, 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.

8. 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 II,

Formula II

with alkyl cyano derivative of formula III,

Formula III
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 IV,

Formula IV

b) converting cyano-acrylic acid compound of formula IV to 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula I,
c) optionally crystallizing 3-(2-bromo-4,5-dimethoxybenzene)propionitrile of formula I with a suitable solvent,
d) converting 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula I to ivabradine or pharmaceutically acceptable salt thereof.

9. The process as claimed in claim 8, 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-dimethoxyethane, 1,2-diethoxyethane or mixture thereof.
10. The process as claimed in claim 8, wherein in step b) conversion of cyano-acrylic acid compound of formula IV to 3-(2-bromo-4,5-dimethoxybenzene) propionitrile of formula I is carried out by process as claimed in claims 3 and 5; 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.