WO2014020534A1

WO2014020534A1 - Ivabradine hydrochloride and the processes for preparation thereof

Info

Publication number: WO2014020534A1
Application number: PCT/IB2013/056245
Authority: WO
Inventors: Kiran Kumar Kothakonda; Sivakumar Ramasamy; Sravan Kumar BANDARU; Srinivas Pullela Venkata
Original assignee: Biocon Limited
Priority date: 2012-07-30
Filing date: 2013-07-30
Publication date: 2014-02-06

Abstract

The present disclosure relates to a process of preparing Ivabradine Hydrochloride, which is devoid of product related impurities. More specifically, the present disclosure provides a process to obtain a new polymorph of Ivabradine Hydrochloride, wherein said polymorph is pure and devoid of impurities at particular RRTs. The disclosure further relates to the removal of specific impurities of Formula 8 and/or Formula 9 during the preparation of said Ivabradine Hydrochloride. The disclosure also specifically provides the said polymorphic form of Ivabradine Hydrochloride.

Description

"IVABRADINE HYDROCHLORIDE AND THE PROCESSES FOR

PREPARATION THEREOF"

TECHNICAL FIELD

The present disclosure relates to a process of preparing Ivabradine Hydrochloride, which is devoid of product related impurities. More specifically, the present disclosure provides a process to obtain a new polymorph of Ivabradine Hydrochloride, wherein said polymorph is pure and devoid of impurities at particular R Ts. The disclosure further relates to the removal of specific impurities of Formula 8 and/or Formula 9 during the preparation of said Ivabradine Hydrochloride. The disclosure also specifically provides the said polymorphic form of Ivabradine Hydrochloride.

BACKGROUND OF THE DISCLOSURE

Angina pectoris, commonly known as angina, is a chest pain due to the obstruction of heart muscle and coronary arteries. Ivabradine Hydrochloride is developed by Servier Laboratories and marketed as Procoralan, Coralan and Corlentor. Ivabradine is a cardiotonic agent, which acts by reducing heart rate in a mechanism different from beta blockers, and calcium channel blockers. Ivabradine and its use for the treatment of myocardial ischemic states was disclosed in prior art.

Many crystalline forms of Ivabradine hydrochloride along with the processes for preparation have been disclosed in the prior art.

The process for preparing Ivabradine is disclosed in prior art. According to the process, (+)-isomer of Ivabradine is treated with dilute HC1 and then recrystallization in acetonitrile leads to the formation of Ivabradine hydrochloride salt having instantaneous m.p. 135-140°C. By following the prior art process, multiple purifications need to be adopted to achieve the desired purity. However, the process taught in prior art generated impurity of the formula 9, which has significant role during the purification. This process employed in prior art teaches to use very dilute HC1 and results in enormous volume, which is difficult to handle during bulk production. The prior art processes for the preparation of polymorphs are tedious and time consuming, and does not address the need to achieve the desired quality with ease of operation. Despite the attempts of the prior art to synthesize pure Ivabradine Hydrochloride, effective synthetic processes of preparing polymorphically pure Ivabradine Hydrochloride are still needed to reduce the steps necessary for synthesis and purification during the bulk production. The current disclosure has answered for such difficulties.

SUMMARY OF THE DISCLOSURE:

Accordingly, the present disclosure relates to a process of preparing ivabradine hydrochloride, said process comprising acts of: a) converting 7,8-Dimethoxy-l,3- dihydro-benzo[d]azepin-2-one (compound of Formula 2) to 7,8-Dimethoxy-3-(3- chloropropyl)-l,3-dihydro-2H-3-benzazepin-2-one (compound of Formula-3) in presence of dimethyl formamide, b) converting the compound of formula-3 to 7,8- Dimethoxy-3-(3-iodopropyl)-l ,3-dihydro-2H-3-benzazepin-2-one (compound of Formula-4), followed by adding (lS)-4,5-Dimethoxy-l-[(methylamino)methyl] benzocyclobutane hydrochloride (compound of Formula-5) to the compound of formula 4 to obtain 3-{3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-l,3,5-trien-7-ylmethyl)- methyl-amino] -propyl} -7, 8-dimethoxy- 1 ,3 -dihydro-benzo [d] azepin-2-one (compound of Formula-6), and c) coverting the compound of formula 6 to 3-[3-({[(7S)-3,4- dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-2-one (compound of Formula 7) followed by reacting the compound of formula 7 with hydrochloric acid to obtain said ivabradine hydrochloride; a process of preparing 7,8-Dimethoxy-3-(3-chloropropyl)- l,3-dihydro-2H-3-benzazepin-2-one (Formula-3), said process comprising act of: reacting 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (Formula 2) with potassium tert-butoxide and l-bromo-3-chloropropane in presence of dimethyl formamide to obtain 7,8-Dimethoxy-3-(3-chloropropyl)- 1 ,3-dihydro-2H-3-benzazepin-2-one

(Formula-3); and an ivabradine hydrochloride polymorphhaving impurity at R T 1.41 of less than 0.20%. BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES:

Figure 1 illustrates a chromatogram to mention R T 1.41 impurity at about 0.8% in Ivabradine Hydrochloride. Figure 2 illustrates a chromatogram to mention RRT 1.41 impurity at about 0.06% in Ivabradine Hydrochloride.

Figure 3 illustrates PXRD of Form-A. DETAILED DESCRIPTION OF THE DISCLOSURE:

The present disclosure relates to a process of preparing ivabradine hydrochloride, said process comprising acts of: a) converting 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin- 2-one (compound of Formula 2) to 7,8-Dimethoxy-3-(3-chloropropyl)-l,3-dihydro-2H- 3-benzazepin-2-one (compound of Formula-3) in presence of dimethyl formamide; b) converting the compound of formula-3 to 7,8-Dimethoxy-3-(3-iodopropyl)-l,3- dihydro-2H-3-benzazepin-2-one (compound of Formula-4), followed by adding (1S)- 4,5-Dimethoxy-l-[(methylamino)methyl] benzocyclobutane hydrochloride (compound of Formula-5) to the compound of formula 4 to obtain 3-{3-[(3,4-dimethoxy- bicyclo[4.2.0]octa- 1 ,3,5-trien-7-ylmethyl)-methyl-amino]-propyl} -7,8-dimethoxy- 1 ,3- dihydro-benzo[d]azepin-2-one (compound of Formula-6); and c) coverting the compound of formula 6 to 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7- yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-

2- one (compound of Formula 7) followed by reacting the compound of formula 7 with hydrochloric acid to obtain said ivabradine hydrochloride.

In an embodiment of the present disclosure, the process provides for ivabradine hydrochloride devoid of 7,8-Dimethoxy-5-propyl-3-(3-chloropropyl)-l,3-dihydro-2H-

3- benzazepin-2-one (compound of Formula 8), or compound of formula 9:

In another embodiment of the present disclosure, the process provides for ivabradine hydrochloride wherein impurity at RRT 1.41 ranges from about 0.01% to about 0.20%.

In yet another embodiment of the present disclosure, the conversion of compound of formula-2 to compound of formula-3 comprises acts of: a) adding potassium tert-butoxide and l-bromo-3-chloropropane to the compound of formula-2 in presence of dimethyl formamide to obtain a mixture; and

b) adding water to the mixture of step a) and stirring at varying temperature, followed by filtering and concentrating the mixture to obtain the compound of formula-3.

In still another embodiment of the present disclosure, the conversion of the compound of formula-3 to the compound of formula-4 comprises acts of- a) adding sodium iodide to a mixture of compound of formula-3 and acetone to obtain a mixture; and

b) filtering, concentrating and drying the mixture of step a) to obtain the

compound of formula-4. In still another embodiment of the present disclosure, the conversion of the compound of formula 4 to the compound of formula-6 comprises acts of:

a) combining the compound of formula-4 and compound of formula-5 in

presence of acetone and potassium carbonate to obtain a mixture; b) filtering, concentrating and extracting the mixture of step a) with

ethylacetate; and

c) washing the extract of step b) and concentrating under vacuum to obtain the compound of formula-6.

In still another embodiment of the present disclosure, the conversion of the compound of formula 6 to the compound of formula-7 comprises acts of:

a) adding palladium hydroxide to a mixture of the compound of formula-6 and acetic acid, followed by hydrogenating the mixture;

b) filtering, concentrating and extracting the reaction mixture of step a) with ethylacetate; and

d) washing the extract of step b) and concentrating under vacuum to obtain the compound of formula-7.

In still another embodiment of the present disclosure, the conversion of the compound of formula-7 to ivabradine hydrochloride comprises acts of- a) adding hydrochloric acid to the compound of formula 7, followed by stirring and filtering to obtain a residual mass;

b) adding acetonitrile to the mass of step a) followed by further stirring and filtering to obtain a filtrate;

c) washing the filtrate of step (b) with acetonitrile followed by drying to obtain the ivabradine hydrochloride.

In still another embodiment of the present disclosure, the temperature ranges from about 18°C to about 95°C.

In still another embodiment of the present disclosure, the filtering is carried out through celite bed.

In still another embodiment of the present disclosure, the compound of formula 7 is ivabradine base.

The present disclosure further relates to a process of preparing 7,8-Dimethoxy-3-(3- chloropropyl)-l,3-dihydro-2H-3-benzazepin-2-one (Formula-3), said process comprising act of: reacting 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (Formula 2) with potassium tert-butoxide and l-bromo-3-chloropropane in presence of dimethyl formamide to obtain 7,8-Dimethoxy-3-(3-chloropropyl)-l,3-dihydro-2H-3-benzazepin- 2-one (Formula-3).

In an embodiment of the present disclosure, the reaction step provides compound of formula 3 devoid of 7,8-Dimethoxy-5-propyl-3-(3-chloropropyl)-l,3-dihydro-2H-3- benzazepin-2-one (Formula 8), or compound of formula 9:

The present disclosure further relates to an ivabradine hydrochloride polymorphhaving impurity at RRT 1.41 of less than 0.20%.

In an embodiment of the present disclosure, the impurity at RRT 1.41 is less than 0.05%.

In another embodiment of the present disclosure, the polymorph is Polymorph A. In yet another embodiment of the present disclosure, the Polymorph A has 2Θ values of about 3.99, 7.64, 8.0, 8.36, 10.2, 10.99, 11.78, 13.05, 13.68, 14.33, 14.66, 17.29, 17.8, 19.98, 20.49, 29.52, 29.87, 30.77, 32.48, 32.22, 34.07, 36.56, 38.33. In still another embodiment of the present disclosure, the X-ray diffraction pattern of the polymorph is represented by Figure 3.

The present disclosure relates to a process of preparing ivabradine hydrochloride, which is devoid of impurities. In particular, the obtained ivabradine hydrochloride is devoid of impurity at 1.41R T (described in figure 2).

The disclosure further relates to a polymorphic form of ivabradine hydrochloride, designated as Form-A. In an embodiment, the process of the instant disclosure has reduced number of manufacturing steps when compared to the conventionally known process of preparing ivabradine hydrochloride. Further to the reduced preparation steps, volume of the components employed in the instant disclosure is drastically reduced, which helps the process to be carried out in larger batches during manufacturing.

In an embodiment, due to lesser volume usage of the components in the instant process, the duration for distillation & the quantity of water to be distilled is considerably reduced. In an embodiment, the process of the instant disclosure prepares ivabradine hydrochloride which has negligible to no impurities, wherein the impurities are product related impurities. As the impurities are reduced/nullified during the preparation steps, the obtained ivabradine hydrochloride does not require further purification steps. In an embodiment, the current disclosure achieves the desired quality of pure ivabradine hydrochloride with minimum number of purifications and enhances the yield.

The number of purification steps is reduced/nullified due to better control over a specific impurity of formula 9. This impurity is controlled during the preparation of the intermediate formula 3. The processes involved in preparing ivabradine hydrochloride in the prior art carry many disadvantages and thus there is a need to arrive at an improved methodology to arrive at such therapeutic compound. Some of the disadvantages of the prior art and the corresponding advantages of the instant invention are:

• The prior art does not disclose the preparation procedure of active pharmaceutical ingredient (API) of Ivabradine Hydrochloride, which meets all the specifications for therapeutic purposes. More over the process produced the material having the melting point (instantaneous): 135-140°C. The disclosed detailed procedure in J. Med. Chem 1990 also does not specify the purity of the final API. The disclosed procedure results in the final product having an impurity at RRT 1.41%, at about 1 % (Figure- 1). On the contrary, the process of the instant disclosure, discloses a procedure to obtain ivabradine hydrochloride with greater melting points and which is devoid of impurity at RRT 1.41.

• Further, the ivabradine hydrochloride obtained by the conventional process did not meet the acceptable limits by various regulatory guidelines such as ICH, which is crucial for the therapeutic use and removal of the unknown and undesired impurity from the finished product, and multiple purification steps had to be performed which would increase the manufacturing cost drastically. On the other hand, ivabradine hydrochloride obtained from the instant process meets all the regulatory guidelines (as described in the embodiments below) and the process disclosed is robust and commercially viable.

In an embodiment of the present disclosure, Ivabradine Hydrochloride is 3-[3-({[(7S)- 3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-2-one Hydrochloride salt, having the molecular formula: C27H36N2O5, and the molecular weight: 468.59 g/mol.

In an embodiment, ivabradine hydrochloride obtained by the process of the instant disclosure is having a purity of about 95%. In an embodiment, melting point of ivabradine hydrochloride obtained by the process of the instant invention is about 189.7 - 191.3°C (187 °C: Initial; 198 °C: final), wherein the limit being 191±3°C. In an embodiment, the residue on ignition (ROI) for the ivabradine hydrochloride obtained by the process of the instant disclosure is about 0.07%, wherein the limit being NMT 0.10%

In an embodiment, the process of the instant disclosure employs celite bed for the filtration of intermediates obtained and the final product, ivabradine hydrochloride.

In an embodiment, the ivabradine hydrochloride obtained by the process of the instant disclosure is having a yield of about 50-60%). In an embodiment of the present disclosure, the ivabradine hydrochloride obtained by the process of the instant disclosure has the specified impurity RRT 1.41 at about less than 0.15%, more specifically not more than 0.10%, most specifically not more than 0.05%) (as described in Figure 2). In another embodiment, the present disclosure relates to the preparation of quality Ivabradine HC1, which has the impurity at RRT 1.41 less than 0.15% and a novel polymorph.

Further, the solid state physical properties of Ivabradine HC1 are influenced by controlling the conditions under which Ivabradine HC1 is obtained in a solid form. Solid state physical properties include, for example, the flowability of the milled solid. Another important solid state property of a pharmaceutical compound is its rate of dissolution. The rate of dissolution of an active ingredient in a patient's stomach fluid has therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient reaches the patient's bloodstream. The solid state form of a compound also affects its behaviour on compaction and its storage stability. These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientational factors in turn result, in particular, in intramolecular interactions and intermolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form gives rise to distinct spectroscopic properties that is detectable by powder X-ray diffraction, solid state ¹³C NMR spectrometry and infrared spectrometry. The polymorphic form also gives rise to thermal behaviour different from that of the amorphous material or another polymorphic form. Thermal behaviour is measured in the laboratory by such techniques as melting point, thermo-gravimetric analysis (TGA) and differential scanning calorimetry (DSC) and is used to distinguish some polymorphic forms from others.

In an embodiment, the ivabradine hydrochloride is obtained by the process of the instant disclosure by following the process of scheme 1 below:

In an embodiment, the impurity of formula 9 is formed during the preparation of formula-3 from formula 2:

Formula-2 Formula-3

In an embodiment, the specified impurity formation is controlled in reaction described by the instant process, by developing the efficient process of preparing formula-3. The specified impurity at RRT 1.41 is not observed upon obtaining the finished product. After isolation of specific impurity and characterizing the same by 1H NMR, ¹³C NMR, it is understood that the impurity is {7,8-Dimethoxy-5-propyl-3-(3-chloropropyl)-l,3- dihydro-2H-3-benzazepin-2-one}, having mass of 511.3 (M+l), which is designated as formula-8 below:

The impurity designated has formula-8 is a result of the corresponding impurity of formula-9, which forms by the C-alkylation of formula-2 in the due course of Formula- 3 preparation. Such C-alkylation of Benzazepin-2-one moiety is not conventionally known. Hence controlling this impurity formation is essential to obtain substantially pure ivabradine hydrochloride and a form devoid of such impurity

The instant disclosure has thus optimized the reaction conditions of obtaining Formula 3 from Formula 2. With this optimization, the impurity is controlled to <0.05% (most of the times not detected) which resulted in the number of recrystallizations in the processes of the prior art. The prior art literature suggests addition of Formula 2 in DMSO/KtOBu was to 3-Bromo-l-Chloro propane in DMSO/KtOBu which resulted in 0.82% of impurity of formula 9. The subsequent formation of the impurity at the final stage requires the recrystallization not less than about 8 times. Thus, the present disclosure is able to arrive at a process of obtaining compound of Formula 3 from compound of Formula 2 with minimal amount of such impurity, thereby the instant disclosure provides a process to overcome the drawbacks of the prior art.

In an embodiment, the process of the instant disclosure employs dimethyl formide (DMF) as a solvent and sequential addition of all the substrate & reagents (KtOBu) based on the progress reaction. The solvent DMF and sequential addition of substrate & potassium tert- butoxide results in well controlled reaction with minimum formation of by-products, specifically impurity of formula 9. In an embodiment of the present disclosure, process for the preparation of formula-3 having the impurity NMT 0.15%, more specifically NMT 0.10%, most specifically NMT 0.02%) is disclosed. Ivabradine Hydrochloride obtained from the new procedure has impurity at R T 1.41 at less than 0.10% level, which avoids additional purification of the finished product. Moreover, the final material is substantially pure and meets all the regulatory guidelines.

In an embodiment, Ivabradine Hydrochloride obtained by the process of the instant disclosure is found to be crystalline in nature. The obtained crystalline ivabradine hydrochloride is subjected to x-ray diffraction, and 2Θ values observed were analysed. Upon analysis it is found that the ivabradine hydrochloride obtained in the instant disclosure is a novel polymorph and does not match the 2Θ values of any reported polymorphic forms of Ivabradine Hydrchloride. The instant polymorphic form has the melting point (instantaneous): 192.5 ±2 °C In an embodiment,, the novel polymorph obtained by the process of the instant disclosure is designated as Form-A (Figure-3) having the 2Θ values at about: 3.99, 7.64, 8.0, 8.36, 10.2, 10.99, 11.78, 13.05, 13.68, 14.33, 14.66, 15.22, 16.37, 16.82, 17.29, 17.8, 18.04, 19.20, 19.98, 20.49, 21.01, 21.28, 21.8, 22.26, 22.93, 23.26, 23.58, 24.19, 24.62, 24.90, 25.42, 25.76, 26.38, 27.57, 28.38, 28.83, 29.52, 29.87, 30.77, 32.48, 32.22, 34.07, 36.56, 38.33. More specifically X-ray diffraction data having the 2Θ values at about: 3.99, 7.64, 8.0, 8.36, 10.2, 10.99, 11.78, 13.05, 13.68, 14.33, 14.66, 17.29, 17.8, 19.98, 20.49, 29.52, 29.87, 30.77, 32.48, 32.22, 34.07, 36.56, 38.33.

In another embodiment of the present disclosure, about 1 N HC1 is added to Ivabradine free base, stirred for 1-2 hours for hydrochloride formation and complete dissolution of the solid in the aqueous medium. The reaction mixture is filtered through celite bed to remove the un-dissolved particles, and reaction mass is concentrated from about 1.1 to about 1.3 w/w under reduced pressure. Acetonitrile is added, and the mass is concentrated again from about 1.1 to about 1.3 w/w under reduced pressure. The acetonitrile addition is repeated to remove the water until the solid is precipitated. Finally acetonitrile is added to the reaction mass and the suspension is heated for about lhour, and thereafter allowed to cool. The solid is filtered and washed with acetonitrile, and the wet cake is sucked dry at about 80°C to about 110 °C till the residual solvents are met as per the ICH guidelines, more specifically 85-100 °C, and most specifically at 90-100 °C.

The volumes of acetonitrile used are from about 1 to about 8 Volumes, more specifically about 1-6 volumes, most specifically about 2-5 volumes.

The acetonitrile strip off temperature is maintained from about 45 to about 65 °C, more specifically about 50-65 °C, most specifically about 50-60 °C.

The moisture content of the final reaction mass is maintained at less than about 2%, more specifically NMT 1%, most specifically NMT 0.5%.

The reaction suspension in acetonitrile is heated from about 73 to about 83 °C, more specifically 75-83 °C, most specifically 76-82 °C. In an embodiment, the method of analysis employed by the process of the instant disclosure to study ivabradine is:

Mobile phase A: 0.1% H₃P0₄ in water, pH 3.0 with TEA; B: Acetonitrile.

Column: Inertsil ods, 250 X 4.6 X 5μ (SCA/LC/164), wavelength: 210 nm, p' 108; Diluent: ACN:water (6:4),

Column temp : 25 °C . P~ 100; Gradient method.

EXAMPLES:

Example 1: Preparation of 7,8-Dimethoxy-3-(3-chloropropyl)-l,3-dihydro-2H-3- benzazepin-2-one (Formula-3)

30 g (0.137mol) 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (Formula 2) is added to 21ml of dimethyl formamide. Potassium tert-butoxide (19.96g, 0.178mol.) is added into the mass at 25°C. Exothermicity is observed and the mass is stirred for 30- 45mins. To the mass, l-bromo-3-chloropropane (24.76g, 0.157mol.) is added at a temperature of less than 40°C, preferably between 20-30°C, and the mass is stirred for 45min. Based on the progress of the reaction, potassium tert-butoxide is further added and stirred for 45min. The reaction mixture is added into 657ml. of water at 25 - 35°C. The mass is stirred for 60min at same temperature followed by cooling the mixture to 18 - 22°C and stirred for 45min. The mass is filtered and the wet material is washed with water. The wet material on drying resulted in 32.38g (80%) of 7,8-Dimethoxy-3-(3-chloropropyl)- l,3-dihydro-2H-3-benzazepin-2-one (Formula-3), having the purity > 90%, containing the corresponding impurity of formula 9 < 0.05%.

EXAMPLE-2: Preparation of 7,8-Dimethoxy-3-(3-iodopropyl)-l,3-dihydro-2H-3- benzazepin-2-one (Formula-4)

7,8-Dimethoxy-3-(3-chloropropyl)- 1 ,3-dihydro-2H-3-benzazepin-2-one (Formula-3) (15g, 0.0507mol.) is added in 90ml. of Acetone. Sodium iodide (19g, 0.1268mol.) is added to the mass and stirred the mass at 55 - 58° for 20hr.

The reaction mass is filtered through celite bed at 35 - 40°C. Filtrate is concentrated under reduced pressure at 45 - 50°C to residual volume of about 3 - 4vol. To the mass, 300ml of water is added at 25 - 30°C and stirred for 2hr. The mass is filtered and the wet material washed with water. The wet material on drying resulted in the yield of about 17.67g (90%>) of 7,8-Dimethoxy-3-(3-iodopropyl)-l,3-dihydro-2H-3-benzazepin- 2-one (Formula-4) having the purity >90%. Example 3: Preparation of 3-{3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-l,3,5-trien-7- ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-l,3-dihydro-benzo[d]azepin-2- one (Formula-6)

7,8-Dimethoxy-3-(3-iodopropyl)- 1 ,3-dihydro-2H-3-benzazepin-2-one (Formula-4) (17.8g, 0.0456mol.) is added with (lS)-4,5-Dimethoxy-l-[(methylamino)methyl] benzocyclobutane hydrochloride (Formula-5) (9.29g, 0.0381mol.) in about 107ml. Acetone. To the mass, Potassium carbonate (12.7g, 0.0919mol.) is added and stirred for about 3hr. at 55 - 58°C.

The mass is filtered through celite bed at 35 - 40°C. Filtrate is concentrated under reduced pressure at 45 - 50°C to 1.4w/w. To the residual mass, 89ml of ethyl acetate is added and the product is extracted using 3N HC1 solution thrice (89ml, 2 x 35.6ml). The combined aqueous layer is basified using Sodium hydroxide and extracted the product using ethyl acetate thrice (89ml. 2 x 36.5ml). The combined organic layer is washed with water and then concentrated under vacuum at 45 - 50°C to obtain about 19.29g (85%) of 3-{3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-l,3,5-trien-7-ylmethyl)- methyl-amino]-propyl}-7,8-dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (Formula-6) having the purity >75%>

Example 4: Preparation of Ivabradine base (Formula-7)

3- {3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-l ,3,5-trien-7-ylmethyl0-methyl-amino]- propyl} -7,8-dimethoxy-l ,3-dihydro-benzo[d]azepin-2-one (Formula-6) (17.5g, 0.0375mol.) is added with 87.5ml of acetic acid. To the mass, 3.5g of 20%> Palladium hydroxide (dry) is added and hydrogenated under hydrogen pressure of 3 - 4Kg/cm² at 25 - 30°C for 3hr.

The mass is filtered through celite bed. Filtrate is concentrated to 1.4w/w under reduced pressure at 50 - 55°C. To the residual mass. 87.5ml of ethyl acetate is added and the product is extracted using water twice (87.5ml and 52.5ml). The combined aqueous layer is basified using Sodium hydroxide and the product is extracted using ethyl acetate thrice (87.5ml, 2 x 52.5ml). The combined organic layer is washed with water and then concentrated under vacuum at 45 - 50°C to get about 14.94g (85%) of Ivabradine base (Formula-7) having the purity >75%

Example 5: Preparation of Ivabradine Hydrochloride (Formula-1)

To the Ivabradine base (Formula-7) (15g, 0.032mol.), 37.5ml. of IN hydrochloric acid is added. The mass is stirred for lhr and filtered through celite bed. Filtrate is concentrated to about 1.2w/w under reduced pressure at 55 - 60°C. To the residual mass, acetonitrile is added and stripped off to about 1.2w/w thrice (3 x 30ml). 75ml of acetonitrile is added and stirred the mass for lhr at 78 - 82°C. The mass was cooled to 25 - 29°C and stirred for lhr. The mass is filtered and the wet material is washed with acetonitrile. Wet material was dried under vacuum at 85 - 95°C to get 9.7g (60%>) of Ivabradine Hydrochloride (Formula 1) EXAMPLE-6: Preparation of substantially pure Ivabradine Hydrochlorde polymorphic Form-A:

To Ivabradine base of Formula-7 (15 g), about 1 N hydrochloric acid (about 2.5 vol) is added at ambient temperature and stirred for about lhour. The resulting reaction mass is filtered through celite bed to remove undissolved particles. The filtrate is concentrated under reduced pressure at about 55-60 °C to about 1.1 w/w. Acetonitrile (about 2 vol) is added and stripped off to about 1.1 w/w. To the suspension, acetonitrile (about 5 vol) is added and the mass is stirred at about 75-80 °C for about lhour. The resulting solid is filtered, washed with acetonitrile (about 1 vol) and the wet cake is dried at about 85-95 °C until the residue solvents are met as per the ICH limits. The final material is obtained as white crystalline material (Form-A) having the purity of about 99.7% (HPLC), containing the formula I R T 1.41 impurity about 0.06%.

EXAMPLE-7: Preparation of substantially pure Ivabradine Hydrochloride polymorphic Form-A:

About 2 N hydrochloric acid (about 2.5 vol) is added slowly to Ivabradine free base (Formula-7) (200 g) in water (about 2 vol), and then the mixture is stirred for about 1.5hours. The resulting mass is clarified through celite bed and then the filtrate is concentrated to about 1.3 w/w at 45-60°C. The mass is stripped off thrice with acetonitrile (about 2 vol) to about 1.3 w/w until the suspension is observed. Acetonitrile (about 5 vol) is added and stirred at 75-82 °C for about lhour, the reaction mass is cooled, filtered, washed with acetonitrile (about 2 vol), and the cake is dried at about 85-95 °C until the residual solvent limits are met to obtain white crystalline material (aboutl80 g). Upon the analysis of PXRD, the polymorph is found to be Form-A (Figure-3). The purity (HPLC) is about 99.75%, with no impurity at 1.41 RRT. The melting point (instantaneous) is about 192.5 ±2 °C (187 °C: Initial; 198 °C: final).

EXAMPLE-8: Preparation of substantially pure Ivabradine Hydrochloride polymorphic Form-A:

To Ivabradine free base (Formula-7) (500 g), 1 N hydrochloric acid (about 2.5 vol) is added slowly at ambient temperature and stirred for about lhour. The resulting reaction mass is filtered through celite bed and the filtrate is concentrated under reduced pressure at 55-60 °C to about 1.1 w/w. Acetonitrile (about 2 vol) is added and stripped off to about 1.1 w/w. To the suspension, acetonitrile (about 5 vol) is added and the mass is stirred at 73-82 °C for lhour. The resulting solid is filtered, washed with acetonitrile (about 1 vol), the wet cake is dried at 90-95 °C until the residue solvents are met as per the ICH limits. The final material is obtained as white crystalline material (Form- A) having the purity 99.7% (HPLC), containing the 1.41 RRT impurity about 0.02%.

Claims

We Claim:

1. A process of preparing ivabradine hydrochloride, said process comprising acts of:

a) converting 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (compound of Formula 2) to 7,8-Dimethoxy-3-(3-chloropropyl)-l,3- dihydro-2H-3-benzazepin-2-one (compound of Formula-3) in presence of dimethyl formamide;

b) converting the compound of formula-3 to 7,8-Dimethoxy-3-(3- iodopropyl)-l,3-dihydro-2H-3-benzazepin-2-one (compound of Formula-4), followed by adding (lS)-4,5-Dimethoxy-l- [(methylamino)methyl] benzocyclobutane hydrochloride (compound of Formula-5) to the compound of formula 4 to obtain 3-{3-[(3,4- dimethoxy-bicyclo [4.2.0]octa- 1 ,3 ,5 -trien-7-ylmethyl)-methyl-amino] - propyl}-7,8-dimethoxy-l ,3-dihydro-benzo[d]azepin-2-one (compound of Formula-6); and

c) coverting the compound of formula 6 to 3-[3-({[(7S)-3,4- dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7- y ljmethy 1 } (methy l)amino)propy 1] -7 , 8 -dimethoxy-2 ,3,4,5 -tetrahy dro- 1 H- 3-benzazepin-2-one (compound of Formula 7) followed by reacting the compound of formula 7 with hydrochloric acid to obtain said ivabradine hydrochloride.

2. The process as claimed in claim 1, wherein the process provides for ivabradine hydrochloride devoid of 7,8-Dimethoxy-5-propyl-3-(3-chloropropyl)-l,3- dihydro-2H-3-benzazepin-2-one (compound of Formula 8), or compound of formula 9:

The process as claimed in claim 1 , wherein the process provides for ivabradine hydrochloride wherein impurity at RRT 1.41 ranges from about 0.01% to about 0.20%.

The process as claimed in claim 1, wherein the conversion of compound of formula-2 to compound of formula-3 comprises acts of:

a) adding potassium tert-butoxide and l-bromo-3-chloropropane to the compound of formula-2 in presence of dimethyl formamide to obtain a mixture; and

The process as claimed in claim 1 , wherein the conversion of the compound of formula-3 to the compound of formula-4 comprises acts of- a) adding sodium iodide to a mixture of compound of formula-3 and acetone to obtain a mixture; and

b) filtering, concentrating and drying the mixture of step a) to obtain the

compound of formula-4.

The process as claimed in claim 1 , wherein the conversion of the compound of formula 4 to the compound of formula-6 comprises acts of:

a) combining the compound of formula-4 and compound of formula-5 in

presence of acetone and potassium carbonate to obtain a mixture;

b) filtering, concentrating and extracting the mixture of step a) with

ethylacetate; and

The process as claimed in claim 1 , wherein the conversion of the compound of formula 6 to the compound of formula-7 comprises acts of:

a) adding palladium hydroxide to a mixture of the compound of formula-6 and acetic acid, followed by hydrogenating the mixture; b) filtering, concentrating and extracting the reaction mixture of step a) with ethylacetate; and

c) washing the extract of step b) and concentrating under vacuum to obtain the compound of formula-7.

8. The process as claimed in claim 1, wherein the conversion of the compound of formula-7 to ivabradine hydrochloride comprises acts of- a) adding hydrochloric acid to the compound of formula 7, followed by stirring and filtering to obtain a residual mass;

9. The process as claimed in any of the claims 4 to 8, wherein the temperature ranges from about 18°C to about 95°C.

10. The process as claimed in any of the claims 4 to 8, wherein the filtering is

carried out through celite bed.

11. The process as claimed in claim 1 , wherein the compound of formula 7 is ivabradine base.

12. A process of preparing 7,8-Dimethoxy-3-(3-chloropropyl)-l,3-dihydro-2H-3- benzazepin-2-one (compound of Formula-3), said process comprising act of: reacting 7,8-Dimethoxy-l,3-dihydro-benzo[d]azepin-2-one (compound of Formula 2) with potassium tert-butoxide and l-bromo-3-chloropropane in presence of dimethyl formamide to obtain 7,8-Dimethoxy-3-(3-chloropropyl)- l,3-dihydro-2H-3-benzazepin-2-one (compound of Formula-3).

13. The process as claimed in claim 12, wherein the reaction step provides the compound of formula 3 devoid of 7,8-Dimethoxy-5-propyl-3-(3-chloropropyl)- l,3-dihydro-2H-3-benzazepin-2-one (compound of Formula 8), or compound of formula 9:

14. An ivabradine hydrochloride polymorphhaving impurity at RRT 1.41 of less than 0.20%.

15. The ivabradine hydrochloride polymorph as claimed in claim 14, wherein the impurity at RRT 1.41 is less than 0.05%.

16. The ivabradine hydrochloride polymorph as claimed in claim 14, wherein the polymorph is Polymorph A.

17. The ivabradine hydrochloride polymorph as claimed in claim 16, wherein the Polymorph A has 2Θ values of about 3.99, 7.64, 8.0, 8.36, 10.2, 10.99, 11.78, 13.05, 13.68, 14.33, 14.66, 17.29, 17.8, 19.98, 20.49, 29.52, 29.87, 30.77, 32.48, 32.22, 34.07, 36.56, 38.33.

18. The ivabradine hydrochloride polymorph as claimed in claim 16, wherein the X-ray diffraction pattern of the polymorph is represented by Figure 3.

Dated this 30^tn day of July, 2012

DURGESH MUKHARYA

Of K & S Partners

Agent for the Applicant