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

MeCT ^ NCN Formula I
and a process for purification of (S)-iV-[(4,5-dimethoxybenzocyclobut-l-yl)-m ethyl]-iV-(methyl)amine camphosulphonic acid salt of formula II.

Me°^^^ CSA Formula II

H
MeO'
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride, of formula III has very valuable pharmacological and therapeutic properties and is chemically known as (,S)-7,8-dimethoxy-3-{3-{jV-[(4,5-dimethoxybenzocyclobut-l-yl)methyl-jV-(methyl)amino)propyl)l,3,4,5-tetrahydro-2//-3-benzazepine-2-one hydrochloride.


O
N-
N-
Me°Y^rt

■J

.HC1

OMe OMe

Formula III

It is useful in many cardiovascular diseases such as angina pectoris, myocardial infraction and associated rhythm disturbances.
MeO MeO
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 benzocyclobutane intermediates, as shown below in scheme I.
Me(
MeO

BHvTHF/EtOH
g OEt
T
o
MeO'
MeO'
Ethyl chloroformate NH9
CN
LiAlI^/THF

MeO MeO


K2C03, Acetone

MeO
H
NaOH
MeO
O
N-
MeO-^-^^7

(d)-Camphosulfonic acid
Ethanol MeO
H -<
.CSA
MeO
I
Pd(OH)2
Glacial acetic acid
OMe Aq-HC1
OMe
Ivabradine.HCl

SCHEME-1
As represented in scheme 1, ivabradine hydrochloride is prepared by reduction of 4,5-dimethoxy-l-cyano-benzocyclobutane with boron-tetrahydrofuran complex to form 4,5-dimethoxy-l-(methyl amine)-benzocyclobutane; which upon condensation with ethyl chloroformate and further reduction with lithium

aluminium hydride in tetrahydrofuran 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-2//-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.
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-bromo-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.
Another article, namely Tetrahedron 1973 (29) pp. 73-76 discloses a process for preparation of 4,5-dimethoxy-l-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. Xhe above article is completely silent about purity and assay of resulting cyano product.
US patent 8,198,485 discloses resolution of methyl amine derivative by using di-p-toluoyl-L-tartaric acid salt.
A PCX publication WO2008/065681 discloses a process for the preparation of ivabradine and its pharmaceutically acceptable salts by using intermediate (S)-iV-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-jV-(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. Xhis PCX application is silent about the purity and yield of camphosulphonic acid salt of methyl amine derivative.
PCX publication WO2010/072409 discloses resolution of methyl amine derivative by using mandelic acid salt.
PCX publication WO2011/138625 discloses a process for preparation of 4,5-dimethoxy-1-cyano-benzocyclobutane, by reacting 2-bromo-4,5-dimethox-phenylpropionitrile 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.
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 hydrochloride 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 hydrochloride are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the 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-1-cyano-benzocyclobutane, 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
6

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 hydrochloride 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-1-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 hydrochloride, 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 hydrochloride 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
7

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 above, 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 hydrochloride.
Another object of present invention is to provide an improved process for purification of 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I having improved assay and purity.
Another object of present invention is to provide an improved process for purification of 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I by avoiding use of column chromatographic techniques.
8

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)-#-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-#-(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)-#-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-#-(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 hydrochloride using highly pure 4,5-dimethoxy
benzocyclobutane derivatives.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for purification of 4,5-dimethoxy benzocyclobutane derivatives, which are important intermediates in the preparation of ivabradine hydrochloride.
According to one embodiment, the present invention provides a process for purification of 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I.
JL ^J—I Formula I
which is an important intermediate in the preparation of ivabradine hydrochloride
9

According to one other embodiment, 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 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; and
i) isolating pure 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I.
According to one other embodiment, 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 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) 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-1-cyano-benzocyclobutane of formula I.
10

According to another embodiment, present invention provides a process for the preparation of ivabradine hydrochloride, 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-1-cyano-benzocyclobutane of formula I; and
j) converting pure 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I in to
ivabradine hydrochloride of formula III.
According to one other embodiments, present invention provides a process for
purification of (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-
(methyl)amine camphosulphonic acid salt of formula II.


MeO MeO

.CSA
\^N^ Formula II

which is a key intermediate in the preparation of ivabradine hydrochloride of formula III.
According to one other embodiment, the present invention provides a process for
purification of (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-
(methyl)amine camphosulphonic acid salt of formula II, comprising the steps of:
11

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 another embodiment, present invention provides a process for the preparation of ivabradine hydrochloride of formula III, 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;

e) isolating pure camphosulphonic acid salt of formula II; and
f) converting pure methyl amine camphosulphonic acid intermediate in to ivabradine hydrochloride of formula III.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for purification of 4,5-dimethoxy benzocyclobutane derivatives, which are important intermediates in the preparation of ivabradine hydrochloride.
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.
12

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.
13

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-1-cyano-benzocyclobutane of formula I, is highly pure and displays comparatively high percentage of assay. The intermediate may have purity more than 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 hydrochloride in high purity having undesired impurities in acceptable amounts or free from the impurities.
In one other embodiment, pure 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I is converted into pure ivabradine hydrochloride.
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.
14

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; C1-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 -C4 aliphatic nitrile solvents such as acetonitrile, propionitrile and the like; of which methanol is preferred. The antisolvent 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-C10 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
for purification of (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-
(methyl)amine camphosulphonic acid salt of formula II, using a mixture of alcoholic solvent and ether as antisolvent.
15

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 oC to reflux temperature. The resulting reaction mass can be
further refluxed for 10 minute to 2 hours. Thereafter reaction mass is cooled to
30-35oC and stirred for 15 minutes to 4 hours at same temperature. The purified
product can be isolated from the 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. All impurities have potential to further react in usual
reaction sequence leading the final API i.e. ivabradine hydrochloride.
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 hydrochloride with high
purity.
In one other embodiments, the invention provides an improved process for the
preparation of pure (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-
(methyl)amine camphosulphonic acid salt of formula II,
16

Generally, the process comprises reduction of pure 4,5-dimethoxy-1-cyano-benzocyclobutane of formula I, in the presence of catalyst, a base in a suitable solvent to form 4,5-dimethoxy-1-(methyl amine)-benzocyclobutane compound of formula IV,

MeO
Formula IV
MeO
^NH2
protecting the intermediate of formula IV with boc anhydride in the presence of a suitable solvent to form intermediate of formula V, MeO
v H
MeO
Formula V
O
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,
MeO

VHN Formula VI
MeO
reacting corresponding methyl amine intermediate of formula VI with
camphosulphonic acid in the presence of suitable solvent to form racemic (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine camphosulphonic acid salt, purifying 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 hydrochloride of formula III. 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
17

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 of 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 C1-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/cm2 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-dimethyl ether, 1,2-diethyl ether, disopropylether, tertiary butyl methyl ether and the like.
18

The reaction can be carried out from 0 oC 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-methyl tetrahydrofuran, 1,2-dimethylether, 1,2-diethylether; 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 -5oC to 10oC and further treated with dimineralized water. Dimineralized water (DM water) is slowly added at 0-15oC followed by addition of aqueous sodium hydroxide solution, further reaction mass is stirred at 10oC to 45oC 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 product.
19

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; C1-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 can be carried out 0oC 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
20

which is further provided by the present invention a pharmaceutical composition comprising ivabradine hydrochloride of formula III.
The main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of ivabradine hydrochloride by using highly pure 4,5-dimethoxy-1-cyano-benzocyclobutane derivatives. Further, present invention provides highly pure 4,5-dimethoxy-1-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.
EXAMPLES:
EXAMPLE 1: Purification of 4,5-dimethoxy-1-cyano-benzocyclobutane
Crude 4,5-dimethoxy-1-cyano-benzocyclobutane (1.0Kg) was dissolved in toluene (7.0L) at 60-65oC. Silica gel (0.50Kg) and activated carbon (0.10Kg) were successively added. The reaction mass was further stirred at 60-65oC 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 0-5oC and stirred at same temperature for 60 minutes. The resulting solid was filtered, washed with hexane (0.50L) and dried under vacuum at 60-65oC for eight hours to obtain title compound as cream coloured powder, having purity 99.9% by HPLC and assay 99.3% w/w.
EXAMPLE 2: Preparation of 4,5-dimethoxy-1-(methyl amine)-
benzocyclobutane
Pure 4,5-dimethoxy-1-cyano-benzocyclobutane (100g), methanol (800ml), sodium hydroxide (10.0g) and Raney nickle (20.0g) were charged in the autoclave
21

and stirred under 4.0-5.0 Kg./cm2 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-1-(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 finally the oily residue was degassed under reduced pressure.
EXAMPLE 3: Preparation of boc protected 4,5-dimethoxy-1-(methyl amine)-benzocyclobutane
4,5-Dimethoxy-1-(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 10-20oC and stirred for 60 minutes. The solid was filtered, washed with n-hexane (100 ml) and finally dried at 50-60 oC to obtain boc protected 4,5-dimethoxy-1-(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-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl) amine
Boc-protected 4,5-dimethoxy-1-(methyl amine)-benzocyclobutane (132g) was
dissolved in tetrahydrofuran (0.39L). In a separate RBF, lithium aluminium hydride (34.0g) was taken in tetrahydrofuran (500ml) under inert atmosphere and was heated to reflux temperature. The solution of boc protected 4,5-dimethoxy-1-(methyl amine)-benzocyclobutane, prepared above, was added slowly to the
22

reaction mass and then the reaction mass was further refluxed for 2 hours. After completion of reaction, the reaction mass was cooled to 0oC. DM water (139ml) was added slowly at 0-15oC followed by addition of 20% aqueous sodium hydroxide solution (25g). The reaction mass was further stirred at 10-25oC 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-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine
A solution of boc-protected 4,5-dimethoxy-1-(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 75oC and maintained the temperature of the reaction mass between 75-90oC. After completion of addition, the reaction mass was stirred at 80-90oC. After reaction completion, the reaction mass was cooled to 0-5oC. Dilute aqueous sodium hydroxide solution (8.0g in 1.0L) was added slowly at 0-20oC 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 with 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-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine camphosulphonic acid salt
To a solution of 4,5-dimethoxybenzocyclobut-1-yl-methyl-N-methylamine (88g) in ethanol (300ml), D-(+) camphorsulphonic acid (112g) was added and the
23

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 vacuum to obtain title compound as a white to off white solid, having chiral purity 61.70% by HPLC.
EXAMPLE 7: Purification of crude (S)-JV-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-JV-(methyl)amine camphosulphonic acid salt A suspension of crude (S)-jV-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-jV-(methyl)amine camphosulphonic acid salt (HOg) in methanol (110ml) 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%.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

WE CLAIM:

A process for purification of (S)-iV-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-jV-(methyl)amine camphosulphonic acid salt of formula II,

MeCk ^^p_^ .CSA
MeO'
\^N^ 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.
The process as claimed in claim 1, wherein in step a) alcoholic solvent includes C1-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; C5-C10 cyclic or acyclic saturated hydrocarbon solvent such as hexane, heptane, cyclohexane or mixture thereof; in step c) heating temperature is 35 °C to 90 °C.
The process as claimed in claim 1, wherein in step a) alcoholic solvent is preferably selected from methanol, ethanol, n-propanol, isopropanol, or mixture thereof; in step b) antisolvent is preferably isopropyl ether,

tertiarybutyl methyl ether, tetrahydrofuran, dioxane; in step c) heating temperature is preferably 55 °C to 70 °C.
A process for preparation of (R,S)-iV-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-jV-(methyl)amine of formula VI,

MeO
MeO'

Formula VI

mprising the steps of: a) protecting the intermediate of formula IV

MeO
B
MeO'
^

VNH2

Formula IV

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

MeO MeO

Formula V
H
VN^0^
o
b) reducing boc-protected intermediate in a suitable reducing agent and a suitable solvent to get intermediate of formula VI.
) The process as claimed in claim 4, wherein 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, disopropylether, tertiary butyl methyl ether and the like or mixture thereof.

The process as claimed in claim 4, wherein step b) reducing agent includes lithium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, vitride and the like.
The process as claimed in claim 4, wherein 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-dimethyl ether, 1,2-di ethyl ether and the like; aromatic hydrocarbon solvents such as benzene, xylene, toluene and the like or mixture thereof.