FORM 2
THE PATENTS ACT 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
PROCESS FOR THE PREPARATION OF IVABRADINE
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT,
1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR THE PREPARATION OF IVABRADINE
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of Ivabradine
Intermediate i.e. (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-l-yl)
methyl] -N- (methyl) amino} propyl}-!,3-dihydro-2H-3-benzazepin-2-one by coupling
process, and Ivabradine base i.e. 3-{3-[{[(7S)-3,4-Dimethoxy bicycle [4.2.0] octa-1,3,5-
triene-7-yl)methyl}(methyl)amino] propyl}-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-
benzazepin -2- one by reduction process.
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride, 3-{3-[{[(7S)-3,4-Dimethoxy bicycle [4.2.0] octa-1,3,5-triene-7-yl)methyl}(methyl)amino] propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin -2- one hydrochloride of formula-I has very valuable bradycardic properties and these compounds are useful in the treatment or prevention of various clinical situations of myocardial ischemia.

Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine acts by reducing the heart rate in a mechanism different from beta blockers and calcium channel blockers, two commonly prescribed Antianginal drugs. It is classified as a cardiotonic agent.
The preparation and therapeutic use of Ivabradine and its salts have been described in Adir's EP0534859 (US5296482, 1992). The patent describes the synthesis of Ivabradine

hydrochloride of formula I, by reacting (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-methyl amine of formula II, with 7,8-dimethoxy-3-[3-iodopropyl]l,3-dihydro-2H-3-benzazepin-2-one of formula-Ill to give (S)-7,8-Dimethoxy-3-{3-{N[(4,5-dimethoxybenzocyclobut-1 -yl)methyl]-N-(methyl)amino}propyl} -1,3-dihydro-2H-3-benzazepin-2-one of formula-IV, which on reduction gives Ivabradine base, that is further converted to its hydrochloride salt.

According to the process, (+) isomer of Ivabradine is treated with concentrated HC1 and then recrystallised from acetonitrile to obtain Ivabradine monohydrochloride salt. '482 discloses the purification of Benzazepine derivative of formula-IV by column chromatography. The patent also discloses the process for the preparation of Ivabradine base by reduction of Benzazepine derivative of formula-IV with palladium hydroxide and glacial acetic acid in ethanol under hydrogen pressure. '482 discloses the purification of Ivabradine base by column chromatography.
Use of palladium hydroxide is fairly expensive in comparison to other reducing agents in large scale production and also use of highly flammable and large quantity of organic solvents in preparation of formula-IV makes this process unattractive.

The disclosed process yields the final compound of formula-I in a very low yield involving three steps from the coupling stage of reacting mefhylamine intermediate with benzazepine-2-one intermediate.
US20050228177 (Lerestif, Jean-Michel et.al, 2005) discloses to a process for the preparation of Ivabradine and its pharmaceutically acceptable acid salts and hydrates, wherein 7,8-dimethoxy-3-substituted-l,3-dihydro-2H-3-benzazepin-2-one derivative is subjected to catalytic hydrogenation to give a reduced derivative, 7,8-dimethoxy-3-substituted-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one derivative, which is then reacted with an acid addition salt of formula-ll in presence of hydrogen and a catalyst in a single step. However, the said process involves a number of steps while converting the above mentioned benzazepine derivative to Ivabradine.
WO2008065681 (Dwivedi, Shriprakash, Dhar et. Al, 2006) discloses the preparation of Ivabradine base via another intermediate of formula-V, 3-Chloro-N-{[(7S)-3,4-dimethoxy bicycle[4.2.0] octa-1,3,5- triene-7-yl] methyl}-N-methyI propan-1-amine with crystalline intermediate of formula-VI, 7,8-dimethoxy-l,3,4,5-tetrahydrobenzo[d]azepin-2-one in presence of a base in a suitable solvent.

WO2008146308 (Singh, Satyendra, Pal et. Al, 2007) relates to a process for the preparation of Ivabradine hydrochloride by initially condensing N-methyl amine derivative of formula-II with benzazepin-2-one derivative of formula-Ill to form compound of formula-IV in presence of base in a suitable solvent. The formula-IV is then catalytically hydrogenated using palladium on carbon in glacial acetic acid to give Ivabradine base which was further converted to its hydrochloride salt of formula-I by reacting with alcoholic hydrogen chloride. This process consist one more steps to convert

7,8-dimethoxy-3-[3-chloropropyl]-l,3-dihydro-2H-3-benzazepin-2-one to its iodopropyl compound for the formation of formula-Ill. Also, this process uses large quantity of Pd on carbon for reduction purposes, which render the process less cost-effective.
As described from the above cited literature, the process for preparation of Ivabradine suffers from several drawbacks like purification of intermediates by column chromatographic techniques, difficulty in scaling up on an industrial scale, use of large measures of catalysts, relatively lower yields in various steps, high volumes of solvents used in some of the steps.
In view of the above, it is therefore desirable to provide an efficient, simple, cost-effective and eco-friendly process for the preparation of pure Ivabradine base.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient, industrially scalable and advantageous process for the preparation of pure Ivabradine intermediate, its oxalate salt and its free base.
Another object of the present invention is to provide a cost-effective and eco-friendly process for the preparation of pure Ivabradine intermediate, its oxalate salt as well as its
free base.
Yet another object of the present invention is to provide an efficient, cost-effective and eco-friendly and industrially scalable process for the preparation of pure Ivabradine base.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-l-yl) methyl] -N- (methyl) amino} propyl}-l,3-

dihydro-2H- 3-benzazepin-2-one, formula-IV, an intermediate of Ivabradine hydrochloride (Formula-I)

comprising the steps of
a) reacting (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-methyl amine of formula-II

with 7,8- dimethoxy- 3-[3-chloropropyl]- 1,3- dihydro- 2H-3-benzazepin-2-one, of formula-VII, in presence of a inorganic base and a catalyst in a dipolar protic solvent at a moderate temperature;

b) purifying compound of Formula-IV of step a) by converting it into its oxalate salt using oxalic acid in suitable organic solvent or mixtures thereof;


c) converting the oxalate salt of formula-IX of step b) into its free base by aqueous inorganic base and
d) extracting the free amine in an organic solvent.
Further, the present invention relates to an improved process for the preparation of Ivabradine base of formula- VIII,

which comprises reduction of the C=C of Benzazepine-2-one ring of compound of formula-IV,

a) with palladium on carbon in the presence of an organic acid, alcoholic solvent and an inorganic acid catalyst under hydrogen atmosphere; or

b) with palladium on carbon with hydrazinium formate in highly polar solvents, an inorganic acid catalyst and a catalyst at a high temperature without using hydrogenator (an autoclave). Further, the present invention also provides an oxalate salt of formula-IX.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an efficient, cost effective and industrially advantageous process for the preparation of pure Ivabradine intermediate and Ivabradine base. Also, the process covered in the present invention is comparatively better to that of prior are reported processes, especially during its large scale production, as the storage and handling of the reagents, chemicals and intermediates is quite safe.


The present invention, represented in Scheme-I, relates to an improved process for the preparation of formula-VIII by using formula-II as a starting material, in presence of an inorganic base, catalyst and dipolar protic solvents. The inorganic base can be selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate preferably sodium carbonate, potassium carbonate, more preferably potassium carbonate. The dipolar protic solvents are selected from N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide and N-methyl pyrrolidone, preferably N-methyl pyrrolidone, in the presence of catalyst like sodium iodide, cuprous iodide, potassium iodide, more preferably potassium iodide. The reaction is conducted at room temperature to 75°C, more preferably in the range of 45-65°C. The completion of the reaction is monitored by HPLC. The organic solvent used for

extraction of reaction mixture is selected from halogenated hydrocarbon such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably ethyl acetate and methylene dichloride.
An embodiment of the invention is to provide the process for purification of intermediate of formula-I V by making oxalate salt (Formula IX) of the same by using oxalic acid in mixture of solvents.

The organic solvents used are selected from acetone, methanol, ethanol, isopropanol, t-butanol, and aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, preferably in acetone, ethyl acetate and mixture there of at a slightly moderate temperature i.e. between of 40-70°C preferably 50-60°C. The reaction mass is cooled, the solid washed and dried to get its salt, which is further converted to its base by using alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate or alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, preferably sodium hydroxide. The product is extracted with organic solvent which is selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, preferably methylene chloride to get the purified intermediate, formula-I V.

Another embodiment of present invention is to provide a novel process for the preparation of formula-VIII, which comprises reduction of the C=C function in the earlier stage of formula- IV using hydrogenator. It involves the reduction of (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-l-yl) methyl] -N- (methyl) amino} propyl}-l,3-dihydro-2H- 3-benzazepin -2- one, compound of formula-IV with 10% Pd on carbon in the range of 15 to 25% preferably 20% in formic acid and perchloric acid in suitable organic solvent. The reaction solvent is selected from C1-C4 alcohols like methanol, ethanol, propanol, butanol, preferably ethanol and at the moderate temperature of the reaction in range of 30-60°C, preferably 30-35°C. The hydrogen pressure during the reaction is about 6.0 kg. The progress of the reaction is monitored by HPLC. The reaction mixture is filtered over celite bed, washed with ethanol, quenched into water and made alkaline using an aqueous base which is selected from alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate or alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide. The reaction mass is extracted with solvent selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably methylene dichloride. The distillation of the solvent gives oily residue of formula-VIII.
Yet another embodiment of present invention is to provide a novel process for the preparation of formula-VIII, which comprises reduction of the earlier stage of formula-IV, without using hydrogenator. It involves the reduction of (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-l-yl) methyl] -N- (methyl) amino} propyl}-l,3- dihydro-2H- 3-benzazepin -2- one, compound of formula-IV, using palladium on carbon and hydrazinium formate as a reducing agent in highly polar solvents like ethylene glycol, diethylene glycol, preferably ethylene glycol and inorganic acid catalyst is perchloric acid in presence of suitable catalysts like PEG 100, PEG 200, PEG 400, PEG 800, PEG 1000, PEG 1200 more preferably PEG 400. The hydrazinium formate complex is prepared by using equimolar quantities of hydrazinium hydrate added into formic acid at lower temperature like 0-20°C, preferably 0-10°C. The reaction is carried out in an inert

atmosphere. The reaction mass was heated up to 90-100°C for 2-3 hours. The progress of the reaction is monitored by HPLC. The reaction mixture is filtered over celite bed, washed with ethylene glycol, quenched in water and made alkaline using an aqueous base, which is selected from alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate or alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide. The reaction mass is extracted with the solvent selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably methylene dichloride. The distillation of the solvent gives oily residue of formula-VIII.
Having described the invention with reference to certain preferred embodiments, the other embodiments will become apparent to one skilled in the art from consideration of the specification.
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
EXAMPLES
Example 1: Preparation of (S)-7,8- dimethoxy- 3 - {3 - [ N - [ (4,5-dimethoxy benzocyclobut-1-yl) methyl] -N- (methyl) -amino] propyl } -1,3- dihydro- 2H -3-benzazepin-2-one (IV)
3.0 gm of (lS)-[(4, 5-dimethoybenzocyclobut-l-yl)-methyl]-N-(methyl) amine with 30.0 ml of N-methyl pyrrolidone charged in presence of nitrogen atmosphere in 250 ml RBF. Added 8.0 gm potassium carbonate (dried for 30 min at 100°C) and 2.4 gm of potassium iodide to the reaction mass and stirred the reaction mass for 30 minutes at room temperature. 4.7 gm of 7,8-dimethoxy-3-[3-chloropropyl]-l,3-dihydro-2H-3-benzazepin-2-one in 10.0 mi of N-methyl pyrrolidone was added drop wise (the funnel was rinsed by 5.0 ml of N-methyl pyrrolidone) to the reaction mass. The reaction mass was heated up to

60 to 65°C. The reaction was monitored by TLC/ HPLC On completion of the reaction, the reaction mass was cooled up to room temperature. Filtered and quenched the filtrate in water, extracted the mass with ethyl acetate and added 150.0 ml of 3N hydrochloric acid solution. The aqueous layer was washed with ethyl acetate. The aqueous layer was made alkaline with 20% sodium hydroxide solution and extracted with MDC (3 x 25ml). The combined organic layer was washed with brine, dried over sodium sulphate and the solvent was evaporated to get an oily mass.
The above oily mass (6.0 gm) was charged into 250.0 ml RBF with 30.0 ml of ethyl acetate and heated to 50 to 60°C. The solution of oxalic acid (1.6 gm of oxalic acid in 25.0 ml ethyl acetate and 12.0 ml acetone mixture) was added dropwise at the same temperature. The reaction mass was stirred at 50 to 60°C for 30 minutes and then cooled to RT. The product was filtered and washed with chilled ethyl acetate (50.0 ml). Sucked dry and dried the product at 50°C for 3-4 hours. To the dried product (7.0 gm), 70.0 ml of water was charged in 3 neck RBF and stirred for 5 minutes at room temperature. The reaction mass was basified with 10.0 ml of 20% aqueous sodium hydroxide solution to get the (S)-7,8-dimethoxy-3- {3-{N-[(4,5-dimethoybenzocyclobut-l-yl)-methyl]-N-(methyl) amino] propyl-1,3-dihydro-2H-3-benzazepin-2-one. The reaction mass was extracted with MDC (3 x 200 ml), the organic layer was washed with brine, dried over sodium sulphate and concentrated to give the title compound,(S)-7,8-dimethoxy-3-{3-[N-[(4,5-dimethoxybenzocyclobut-l -yl) methyl] -N-(methyl)-amino]propyl}-l ,3-dihydro-2H-3-benzazepin-2-one. Yield: 85%
Example 2: Preparation of 3-[3-l[[(7S)-3,4-Dimethoxybicyclo[4.2.0octa-l,3,5-trien-7-yl]methyl] methylamino] propyl ]-l,3,4,5 _ tetrahydro -7,8 - dimethoxy- 2H-3-benzazepin-2-one (Ivabradine base).
Process A
(S)-7,8-Dimethoxy-3-{3-[N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(methyl)-amino]propyl}-l,3-dihydro-2H-3-benzazepin-2-one (10.0 gm) with 100.0 ml of Ethanol, followed by 10.0 ml of Formic acid and 2.0 ml of perchloric acid charged into an autoclave. To this, was added 10% Pd/C (1.0 gm) and closed the pressure vessel properly.

Apply 6.0 kg pressure with Hydrogen and stirred it for 13-15 hours at room temperature. The reaction completion was monitored by HPLC. On completion of reaction, filtered the reaction mass over celite bed, washed with ethanol, quenched in water, made alkaline with aqueous sodium hydroxide solution and extracted the reaction mass with MDC. The combined organic layer was washed with brine (80.0 ml), dried over sodium sulphate and concentrated to get the 3-[3-[[[(7S)-3,4-Dimethoxybicyclo[4.2.0octa-l,3,5-trien-7-yl]methyl] methylamino] propyl]-l ,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one.
Process B:
Arranged the four neck RBF with thermometer pocket, stirrer and condenser in oil bath in
nitrogen atmosphere. 10.0 gm of (S)-7,8-Dimethoxy-3-{3-[N-[(4,5-
dimethoxybenzocyclobut-1 -yl) methyl] -N-(rnethyl)-amino]propyl}-l ,3-dihydro-2H-3-
benzazepin-2-one with 80.0 ml of Ethylene glycol, 20.0 ml of PEG 400 and 10.0 ml of
perchloric acid charged into it. To this, 10% Pd/C (3.0 gm) was added and stirred under
nitrogen atmosphere for 10-15 minutes. In another RBF, hydrazinium formate complex
was prepared by adding 12.9 ml of Hydrazine hydrate in 11.9 ml of formic acid at 0 to
5°C. Hydrazinium formate solution was added drop wise to the earlier reaction mass at
room temperature. The reaction mass was heated up to 90-100°C for 2-3 hours. On
completion of the reaction, the reaction mass was filtered over celite bed and quenched
into chilled water. The filtrate was made alkaline by quenching it into aqueous sodium
hydroxide solution (20%) and extracted the mass with MDC. The combined organic layer
was washed with brine (80.0 ml), dried over sodium sulphate and concentrated to give 3-
[3-[[[(7S)-3,4-Dimethoxybicyclo[4.2.0octa-l,3;5-trien-7-yl]methyl] methylamino]
propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one.

We Claim:
1. An improved process for preparing (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-l-yl) methyl] -N- (methyl) amino} propyl}-1,3- dihydro-2H- 3-benzazepin-2-one, formula-IV, an intermediate of Ivabradine hydrochloride (Formula-I)

comprising the steps of
a) reacting (S)-N-[(4,5-dimethoxybenzocycIobut-l-yl) methyl]-N-methyl amine of formula-II

with 7,8- dimethoxy- 3-[3-chloropropyl]- 1,3- dihydro- 2H-3-benzazepin-2-one, of formula-VII, in presence of a inorganic base and a catalyst in a dipolar protic solvent at a moderate temperature;

b) purifying compound of Formula-IV of step a) by converting it into its oxalate salt using oxalic acid in suitable organic solvent or mixtures thereof;


c) converting the oxalate salt of formula-IX of step b) into its free base by aqueous inorganic base and
d) extracting the free amine in an organic solvent.
2. An improved process for the preparation of Ivabradine base of formula- VIII,

which comprises reduction of the C=C of Benzazepine-2-one ring of compound of formula-IV,

a) with palladium on carbon in the presence of an organic acid, alcoholic solvent and an inorganic acid catalyst under hydrogen atmosphere; or

b) with palladium on carbon with hydrazinium formate in highly polar solvents, an inorganic acid catalyst and a catalyst at a high temperature without using hydrogenator (an autoclave).
3. An improved process according to claim la), wherein dipolar protic solvent is
selected from N,N- dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide and
N-methyl pyrrolidone, preferably N-methyl pyrrolidone.
4. An improved process according to claim la), wherein the inorganic base is selected from alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate or alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, preferably sodium carbonate, potassium carbonate, more preferably potassium carbonate.
5. An improved process according to claim la), wherein the catalyst is selected from sodium iodide, cuprous iodide, potassium iodide, more preferably potassium iodide.
6. The process according to claim la), wherein the moderate temperature of the reaction ranges from room temperature to 75°C, more preferably 45-65°C.
7. The process according to claim lb), wherein the reaction temperature of the reaction is between of 40-70°C preferably 50-60°C
8. An improved process according to claim lb), wherein suitable organic solvent selected from C1-C4 alcohols such as methanol, ethanol, propanol, butanol, isopropanol, ketones such as acetone, methylethylketone, methyl isobutyl ketone, aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, preferably is acetone, ethyl acetate and mixture thereof.

9. An improved process according to claim lc), wherein the aqueous inorganic base is selected from alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate or alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, preferably sodium hydroxide.
10. An improved process according to claim Id), wherein organic solvent for extraction is selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, preferably methylene chloride.
11. An improved process according to claim 2a), wherein the quantity of 10% palladium on carbon added is in the range of 15 to 25%, preferably 20% , the organic acid used is formic and the inorganic acid catalyst is perchloric acid
12. An improved process according to claim 2a), wherein the alcoholic solvent is selected from C1-C4 alcohols, preferably ethanol.

13. An improved process according to claim 2a), wherein the moderate temperature of the reaction is in the range of 30-60°C, preferably 30-35°C.
14. An improved process according to claim 2b), wherein highly polar solvent is selected from ethylene glycol, diethylene glycol, preferably ethylene glycol and the inorganic acid catalyst is perchloric acid.
15. An improved process according to claim 2b), wherein catalysts is selected from PEG 100, PEG 200, PEG 400, PEG 800, PEG 1000, PEG 1200, more preferably PEG 400.
16. An improved process according to claim 2b), wherein the reaction is carried out at 80 to 110°C, preferably at 90-100°C.
17. An oxalate salt of formula-IX.


18. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.