Title of Invention	A PROCESS FRO PREPARING CRYSTALLINE IVABRADINE HYDROCHLORIDE
Abstract	The present invention provides a process for preparing Ivabradine of formula (I) or its pharmaceutically acceptable salts, solvates, hydrate thereof, by reacting 3-chloro-N-{[7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropan-1-amine of formula (IV), with 7,8-Dimethoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one of formula (V) or its alkaline salt in presence of base in suitable solvent to provide Ivabradine of formula (I), which can be subsequently converted to its pharmaceutically acceptable salts, solvate or hydrate thereof.

Title of Invention

A PROCESS FRO PREPARING CRYSTALLINE IVABRADINE HYDROCHLORIDE

Abstract

The present invention provides a process for preparing Ivabradine of formula (I) or its pharmaceutically acceptable salts, solvates, hydrate thereof, by reacting 3-chloro-N-{[7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropan-1-amine of formula (IV), with 7,8-Dimethoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one of formula (V) or its alkaline salt in presence of base in suitable solvent to provide Ivabradine of formula (I), which can be subsequently converted to its pharmaceutically acceptable salts, solvate or hydrate thereof.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENT RULES, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "NOVEL CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE" We, CADELA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Sarkhej- Gandhinagar Highway, Ahmedabad - 380015, Gujarat, India. The following specification describes the invention: 1 FIELD OF INVENTION The present invention relates to new crystalline form of Ivabradine hydrochloride of formula (I), solvates ad hydrates thereof. Ivabradine is chemically known as 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl} (methyl)amino]-propyl} -7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride and useful in the treatment of myocardial ischaemia. .HCI (I) The present invention further provides a novel crystalline form of intermediate of Ivabradine having formula (II) and acid addition salt thereof. NHMe MeO MeO S HX0 (II) wherein HX = N-acetyl glutamic acid or camphor sulfonic acid The present invention provides a the novel crystalline form of intermediate of Ivabradine having formula (III) MeO MeO (III) BACKGROUND OF THE INVENTION Ivabradine hydrochloride, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino]-propyl}-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride of formula (I) have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of HCI various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also of various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in the treatment of heart failure. The preparation and therapeutic use of Ivabradine and salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent EP 0 534859. The patent describes the synthesis of Ivabradine hydrochloride by reacting the compound of formula (a) with the compound of formula (b): (a) (b) to give compound of formula (c), the catalytic hydrogenation of which results in Ivabradine. which is then converted into its hydrochloride : This disclosed process yielding Ivabradine hydrochloride in only a very low yield-less than 17% over the 3 steps as a whole. Another process for preparing Ivabradine disclosed in US patent. According to the process, (+) isomer of Ivabradine is treated with aqueous HCI and then recrystallization in acetonitrile leads to the formation of Ivabradine hydrochloride salt having M.P. 135-140 C. 3 US 2005/228177 relates to the process for the preparation of a - crystalline form of Ivabradine hydrochloride which comprises of reacting 3-[2-(l,3-dioxolan-2-yl) ethyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one with ethanol and then followed by addition of (7S)-[3,4-dimethoxybicyclo[4.2.0] octa-l,3,5-trien-7-yl]-N-methylmethan-amine hydrochloride with ethanol and water and final crystallization from toluene / l-methyl-2-pyrrolidinone mixture affords a - crystalline form of Ivabradine hydrochloride. US 2006/0194962 Al relates to a process for the preparation of the [^-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and water or a mixture of Ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallization is complete, and the crystals formed are collected. US 2006/0194963 Al relates also to a process for the preparation of the y-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and 2-ethoxyethanol, a mixture of Ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of Ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the product is collected by filtration. US 2006/0194965 Al discloses a process for the preparation of pd-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and water or a mixture of Ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallization is complete and the crystals thereby formed are collected and dehydrated. US 2006/01945964 Al relates to a process relates also to a process for the preparation of the yd-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and 2-ethoxyethanol, a mixture of Ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of Ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the crystals obtained are collected by filtration and dehydrated. OBJECTS OF INVENTION The object of the present invention is to provide a novel crystalline form of Ivabradine hydrochloride (I) and process fir preparing it. Another object of the present invention is to provide a novel crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic acid. 4 Yet another object of the present invention is to provide a novel crystalline form of (1S)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane camphor sulfonic acid. Further object of the present invention is to provide a crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one. SUMMARY OF THE INVENTION The present invention relates to the preparation of new crystalline, amorphous, hydrates and solvates form of Ivabradine hydrochloride of formula (I), solvates, hydrates, thereof. .HCI (I) The present invention further provides a novel crystalline, amorphous, hydrates and solvates form of intermediate of Ivabradine hydrochloride having formula (II) and acid addition salt thereof. MeO NHMe & MeO HX (II) wherein HX = N-acetyl glutamic acid or camphor sulfonic acid The present invention further provides a novel crystalline, amorphous, hydrates and solvates form of intermediate of Ivabradine having formula (III) MeO- (III) MeO DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel crystalline forms of Ivabradine hydrochloride of formula (I). 5 The present invention provides a novel crystalline forms of Ivabradine hydrochloride, herein after designated as "Form- I" having characteristic X-ray powder diffraction pattern with peaks at 8.6, 9.1, 11.7, 14.6, 17.2, 18.2, 21.5, 23.9, 26.4 and 27.0 +/- 0.2 two theta values. The Form I of Ivabradine hydrochloride is further characterized by X-ray powder diffraction peaks at 11.2, 15.3, 19.6, 20.3, 21.0, 22.2, 22.7, 27.7, 29.4 +/- 0.2 two theta values. According to the embodiment of the present invention, the present invention provides a process for preparing Form I of Ivabradine hydrochloride involves dissolving Ivabradine free base in suitable organic solvent and treated with HCI to form Ivabradine hydrochloride, which is subsequently recrystallized from acetonitrile to the formation of Ivabradine hydrochloride Form-I. The reaction of Ivabradine base with HCI is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting hydrochloride salt. Advantageously, both Ivabradine and the hydrochloric acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Ivabradine and a solvent may be contacted with a hydrochloric acid, or conversely, a mixture, slurry, or solution of hydrochloric acid and a solvent may be contacted with Ivabradine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for hydrochloric acid may be identical with or different from the solvent system used for the Ivabradine.. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two-phase reaction scheme may be used wherein the Ivabradine. and hydrochloric acid are primarily reacted in one phase and the resulting Ivabradine hydrochloric acid compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include a lower alcohol (Ci- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like. 6 According to another embodiment of the present invention, it provides a novel crystalline form of intermediate of Ivabradine hydrochloride having formula (II) and it acid addition salts thereof. NHMe ..© MeO. MeO A, HX wherein HX = N-acetyl glutamic acid or camphor sulfonic acid. The present invention provides a crystalline (lS)-4,5-dimethoxy-l-(methylaminomethyI)-benzocyclobutane N-acetyl-L- gluatamic acid having X-ray powder diffraction pattern with peaks at 8.3, 9.7, 10.7, 12.5, 14.5, 16.0, 16.7, 17.9, 18.7, 19.2, 19.6, 20.4, 21.2, 21.7, 22.7, 23.7, 24.2, 24.6, 25.7, 26.2, 26.7, 28.0, 29.4, 29.8, 30.8, 31.5, 32.4, 33.2, 34.7, 36.0, 36.9, 37.5, 38.3, 39.1 +/-0.2 two theta values. A crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-N-acetyl-L- gluatamic acid having differential scanning calorimetry at 142.42 C. The present invention further provides a crystalline (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic acid having X-ray powder diffraction pattern with peaks at 8.3, 9.7, 10.7, 12.5, 14.5, 16.0, 16.7, 17.9, 18.7, 19.2, 19.6, 20.4, 21.2, 21.7, 22.7, 23.7, 24.2, 24.6, 25.7, 26.2, 26.7, 28.0, 29.4, 29.8, 30.8, 31.5, 32.4, 33.2, 34.7, 36.0, 36.9, 37.5, 38.3, 39.1 +/- 0.2 two theta values. The present invention further provides a crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-camphor sulphonic acid having X-ray powder diffraction pattern with peaks at 7.1, 8.7, 10.9, 14.0, 14.4, 15.0, 17.5, 18.6, 18.9, 20.9, 21.2, 21.4, 22.1, 22.5, 23.9, 24.2, 24.5, 24.9, 25.6, 26.0, 26.6, 27.2, 27.9, 28.5, 29.3, 30.9, 31.4, 31.8, 32.2, 33.6, 34.3, 35.5, 36.5, 37.3, 37.8 +/- 0.2 two theta values. The crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-camphor sulphonic acid having differential scanning calorimetry at 165.78°C In a broader way, yet another aspect of the invention is the novel crystalline form of intermediate of forumla (II) with N-acetyl-L-glutamic acid for the formation of N-acetyl-L-glutamic acid salt of the intermediate of formula 7 0 0HC/^Y^0HHNYCH30 H2N^/ :U In a similar way camphor sulfonic acid salt of intermediate (II) of formula ^o H3C CH3 ^/^Ov V o OH is formed by reacting 4,5-dimethoxy-l-(aminomethyl)benzocyclobutane with camphor sulfonic acid in suitable organic solvent and then recrystallized in a suitable organic solvent to form the novel crystalline form. Novel crystalline form of this acid addition salt by recrystallization in different solvents like alcohol, ketones, esters etc. An another aspect of the invention is the formation of novel crystalline form of intermediate of formula (III) MeO MeO The present invention provides a crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having X-ray powder diffraction pattern with peaks at 4.6, 9.2, 11.3, 11.9, 12.9, 13.2, 13.9, 14.9, 15.4, 16.1, 16.6, 17.1, 18.6, 19.7, 20.1, 20.5, 21.2, 21.8, 22.5, 23.3, 24.5, 25.7, 26.7, 27.0, 28.1, 28.8, 29.9, 30.2, +/- 0.2 two theta values. A crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having differential scanning calorimeter at 196.32 C The present invention provides a process for the preparation of crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having X-ray powder diffraction pattern with peaks at 4.6, 9.2, 11.3, 11.9, 12.9, 13.2, 13.9, 14.9, 15.4, 16.1, 16.6, 17.1, 18.6, 19.7, 20.1, 20.5, 21.2, 21.8, 22.5, 23.3, 24.5, 25.7, 26.7, 27.0, 28.1, 28.8, 29.9, 30.2, +/- 0.2 two theta values, which comprises treating 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one with alkyl acetate and preferably ethyl acetate. 8 The following examples describes the invention specifically and non-limiting in nature.BRIEF BRIEF DESCRIPTON OF THE ACCOMPANYING DRAWINGS Fig.I is a characteristic X-ray powder diffraction pattern for Ivabradine Hydrochloride Form-1. Fig. II is a characteristic differential scanning calorimetry thermogram of Ivabradine Hydrochloride Form-I. Fig. Ill is a characteristic X-ray powder diffraction pattern for crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt. Fig. IV is a characteristic differential scanning calorimetry thermogram of crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt. Fig. V is a characteristic thermal gravimetric analysis of crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt. Fig. VI is a characteristic X-ray powder diffraction pattern for crystalline form of (lS)-4,5-dimethoxy-1 -(methylaminomethyl)-benzocyclobutane-camphor sulphonate salt. Fig. VII is a characteristic differential scanning calorimetry thermogram of crystalline form of (1 S)-4,5-dimethoxy-1 -(methylaminomethyl)-benzocyclobutane-camphor sulphonate salt. Fig. VIII is a characteristic X-ray powder diffraction pattern for crystalline form of 7,8-dimethoxy-1,2,3,4-tetrahydro-2H-3-benzapin-2-one. Fig. IX is a characteristic differential scanning calorimetry thermogram of crystalline form of 7,8-dimethoxy-l ,2,3,4-tetrahydro-2H-3-benzapin-2-one. WORKING EXAMPLES: 1) Preparation of Ivabradine Base In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition tunnel with nitrogen gas inlet, 7,8-Dimethoxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one (Intermediate-B) (81.86 g, 0.37 mole) was added followed by the addition of DMSO (160 ml) at room temperature. Further, Potassium-tert-butoxide (47.45 g, 0.42 mole) was added and a clear solution was observed and solid separates out within 5 min. The reaction mixture was stirred for 1 Hr and after stirring for 1 Hr, 3-(Chloro-propyl)-(3,4-dimethoxy-bicyclo[4.2.0]octa-l(6),2,4-trien-7-ylmethyl)-methyl-amine (Intermediate-A,) (110 g, 0.35 mole) was added being dissolved in DMSO (150 ml) within 1 Hr at 25-30 C. The reaction mixture was stirred for 4-5 Hrs at same temperature condition. After completion of the reaction the reaction mass was added to chilled water (1.5 L) and stirred for 15 min. After stirring the layers were 9 separated and the organic layer was dried on sodium sulfate and solvent was completely distilled out to afford the title compound as Ivabradine base. 2) Preparation of Ivabradine Hydrochloride In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet, Ivabradine Base (lOOg, 0.21 mole) was added followed by the addition of acetonitrile (300 mL) at 20 C. Further, to the reaction mixture IPA HC1 was added drop wise till the pH reaches to 1-2 and the solid was appeared. The reaction mass was cooled to 15-20 C and stirred for 12 Hr at 20 C. After stirring solid was formed and the solid was filtered and washed with acetonitrile under nitrogen atmosphere. Finally, the solid was recrystallized with acetonitrile under reflux condition for 2 Hrs and the solid was filtered and washed with acetonitrile to afford crystalline form of Ivabradine hydrochloride. 3) Preparation of Glutamte salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)- benzocyclobutane In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet (IS)- 4,5-dimethoxy-l-(methyl amino methyl)-benzocyclobutane (100 g, 0.51 mole) and ethanol (2 L) was added. Further, N-acetyl glutamic acid (98.0 g, 0.51 mole) was added and reaction mass was stirred for 6 Hrs at 80 C. The reaction mass was cooled to 25-30 C and further cooled to 20 C and stirred for 8 Hrs and solid comes out. The solid mass was washed with ethanol (30 mL). The wet solid was crystallized with ethanol (800 mL). The reaction mass was cooled to 15-20 C and stirred for 8 Hrs and again the solid was washed with ethanol (40 mL) and dried in hot air oven for 5 Hrs at 60"C. The solid was again recrystallized with ethanol. To the solid mass water was added and further NaOH solution (230 mL) was added and stirred for 15 min. at 20 C. Further to the reaction mass MDC (370 mL) was added and the layers were separated out. MDC layer was washed with water and dried on sodium sulfate and MDC was distilled out completely under vacuum to afford the title compound as Glutamate salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane. 4) Preparation of Camphor sulphonic acid salt of (lS)-4,5-dimethoxy-l-(methyl aminomethyl)-benzocyclobutane In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane (100 g, 0.48 mole) and (+) Camphor sulphonic acid (500 mL) and IPA (500 mL) was added and refluxed for 6 Hrs. The reaction mixture was slowly cooled 10 to room temperature and stirred for 8 Hrs. After stirring the solid washed with IPA and dried in oven at 60 C for 6 Hrs. The solid was added into water (5 L) and basified with NaOH till the pH becomes 12. The reaction was stirred well and extracted with MDC. Finally the solid was dried on sodium sulfate and MDC was distilled out completely to afford Camphor sulphonic acid salt of (3,4-dimethoxy-bicyclo[4.2.0]octa-l(6),2,4-trien-7-ylmethyl)methylamine. 5) Preparation of crystalline salt of 7,8-Dimethoxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet, 7,8-Dimethoxy-2-oxo-l,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (100 g, 0.32 mole) and MDC (350 mL) was added. The reaction mixture was stirred for 15 min. at room temperature. Further the temperature was maintained upto 0-5 C. To the reaction mixture TFA (125 mL) was added drop wise within 2 Hrs at 0-5°C and stirred for 3 Hrs at 0-5°C. To the reaction mixture MDC (2 L) was added and the reaction mass was added into water (500 mL). The layers were separated and to the MDC layer sodium bicarbonate solution (620 mL) was added and again MDC layer was separated out and dried on sodium sulfate and solvent was distilled out completely. Finally to the residue ethyl acetate (250 mL) was added and stirred at 0-5 C for 4 Hrs. The solid was filtered at 0-5 C and finally washed with ethyl acetate to afford the crystalline form of 7,8-Dimethpxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one. H. StmAMANIAM Of SubramaniantfNataraj & Associates leys for the Applicants Dated this the 27th day of November 2006 11

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"NOVEL CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE"
We, CADELA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Sarkhej- Gandhinagar Highway, Ahmedabad - 380015, Gujarat, India.
The following specification describes the invention:
1

FIELD OF INVENTION
The present invention relates to new crystalline form of Ivabradine hydrochloride of formula (I), solvates ad hydrates thereof. Ivabradine is chemically known as 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl} (methyl)amino]-propyl} -7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride and useful in the treatment of myocardial ischaemia.

.HCI

(I)
The present invention further provides a novel crystalline form of intermediate of Ivabradine having formula (II) and acid addition salt thereof.

NHMe
MeO
MeO

S
HX0

(II)
wherein HX = N-acetyl glutamic acid or camphor sulfonic acid
The present invention provides a the novel crystalline form of intermediate of Ivabradine
having formula (III)

MeO
MeO

(III)
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino]-propyl}-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride of formula (I) have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of

HCI

various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also of various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in the treatment of heart failure.
The preparation and therapeutic use of Ivabradine and salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent EP 0 534859. The patent describes the synthesis of Ivabradine hydrochloride by reacting the compound of formula (a) with the compound of formula (b):

(a)

(b)

to give compound of formula (c), the catalytic hydrogenation of which results in Ivabradine. which is then converted into its hydrochloride :

This disclosed process yielding Ivabradine hydrochloride in only a very low yield-less than 17% over the 3 steps as a whole.
Another process for preparing Ivabradine disclosed in US patent. According to the process, (+) isomer of Ivabradine is treated with aqueous HCI and then recrystallization in acetonitrile leads to the formation of Ivabradine hydrochloride salt having M.P. 135-140 C.
3

US 2005/228177 relates to the process for the preparation of a - crystalline form of Ivabradine hydrochloride which comprises of reacting 3-[2-(l,3-dioxolan-2-yl) ethyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one with ethanol and then followed by addition of (7S)-[3,4-dimethoxybicyclo[4.2.0] octa-l,3,5-trien-7-yl]-N-methylmethan-amine hydrochloride with ethanol and water and final crystallization from toluene / l-methyl-2-pyrrolidinone mixture affords a - crystalline form of Ivabradine hydrochloride.
US 2006/0194962 Al relates to a process for the preparation of the [^-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and water or a mixture of Ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallization is complete, and the crystals formed are collected.
US 2006/0194963 Al relates also to a process for the preparation of the y-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and 2-ethoxyethanol, a mixture of Ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of Ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the product is collected by filtration.
US 2006/0194965 Al discloses a process for the preparation of pd-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and water or a mixture of Ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallization is complete and the crystals thereby formed are collected and dehydrated.
US 2006/01945964 Al relates to a process relates also to a process for the preparation of the yd-crystalline form of Ivabradine hydrochloride, which process is characterized in that a mixture of Ivabradine hydrochloride and 2-ethoxyethanol, a mixture of Ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of Ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the crystals obtained are collected by filtration and dehydrated. OBJECTS OF INVENTION
The object of the present invention is to provide a novel crystalline form of Ivabradine hydrochloride (I) and process fir preparing it.
Another object of the present invention is to provide a novel crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic acid.
4

Yet another object of the present invention is to provide a novel crystalline form of (1S)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane camphor sulfonic acid.
Further object of the present invention is to provide a crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one. SUMMARY OF THE INVENTION
The present invention relates to the preparation of new crystalline, amorphous, hydrates and solvates form of Ivabradine hydrochloride of formula (I), solvates, hydrates, thereof.
.HCI
(I)
The present invention further provides a novel crystalline, amorphous, hydrates and
solvates form of intermediate of Ivabradine hydrochloride having formula (II) and acid addition
salt thereof.

MeO
NHMe
&
MeO

HX

(II)
wherein HX = N-acetyl glutamic acid or camphor sulfonic acid
The present invention further provides a novel crystalline, amorphous, hydrates and solvates form of intermediate of Ivabradine having formula (III)
MeO-
(III)
MeO

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel crystalline forms of Ivabradine hydrochloride of formula (I).
5

The present invention provides a novel crystalline forms of Ivabradine hydrochloride, herein after designated as "Form- I" having characteristic X-ray powder diffraction pattern with peaks at 8.6, 9.1, 11.7, 14.6, 17.2, 18.2, 21.5, 23.9, 26.4 and 27.0 +/- 0.2 two theta values. The Form I of Ivabradine hydrochloride is further characterized by X-ray powder diffraction peaks at 11.2, 15.3, 19.6, 20.3, 21.0, 22.2, 22.7, 27.7, 29.4 +/- 0.2 two theta values.
According to the embodiment of the present invention, the present invention provides a process for preparing Form I of Ivabradine hydrochloride involves dissolving Ivabradine free base in suitable organic solvent and treated with HCI to form Ivabradine hydrochloride, which is subsequently recrystallized from acetonitrile to the formation of Ivabradine hydrochloride Form-I.
The reaction of Ivabradine base with HCI is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting hydrochloride salt. Advantageously, both Ivabradine and the hydrochloric acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Ivabradine and a solvent may be contacted with a hydrochloric acid, or conversely, a mixture, slurry, or solution of hydrochloric acid and a solvent may be contacted with Ivabradine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for hydrochloric acid may be identical with or different from the solvent system used for the Ivabradine.. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two-phase reaction scheme may be used wherein the Ivabradine. and hydrochloric acid are primarily reacted in one phase and the resulting Ivabradine hydrochloric acid compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include a lower alcohol (Ci- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like.
6

According to another embodiment of the present invention, it provides a novel crystalline form of intermediate of Ivabradine hydrochloride having formula (II) and it acid addition salts thereof.

NHMe
..©
MeO.
MeO

A,

HX

wherein HX = N-acetyl glutamic acid or camphor sulfonic acid.
The present invention provides a crystalline (lS)-4,5-dimethoxy-l-(methylaminomethyI)-benzocyclobutane N-acetyl-L- gluatamic acid having X-ray powder diffraction pattern with peaks at 8.3, 9.7, 10.7, 12.5, 14.5, 16.0, 16.7, 17.9, 18.7, 19.2, 19.6, 20.4, 21.2, 21.7, 22.7, 23.7, 24.2, 24.6, 25.7, 26.2, 26.7, 28.0, 29.4, 29.8, 30.8, 31.5, 32.4, 33.2, 34.7, 36.0, 36.9, 37.5, 38.3, 39.1 +/-0.2 two theta values.
A crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-N-acetyl-L- gluatamic acid having differential scanning calorimetry at 142.42 C.
The present invention further provides a crystalline (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic acid having X-ray powder diffraction pattern with peaks at 8.3, 9.7, 10.7, 12.5, 14.5, 16.0, 16.7, 17.9, 18.7, 19.2, 19.6, 20.4, 21.2, 21.7, 22.7, 23.7, 24.2, 24.6, 25.7, 26.2, 26.7, 28.0, 29.4, 29.8, 30.8, 31.5, 32.4, 33.2, 34.7, 36.0, 36.9, 37.5, 38.3, 39.1 +/- 0.2 two theta values.
The present invention further provides a crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-camphor sulphonic acid having X-ray powder diffraction pattern with peaks at 7.1, 8.7, 10.9, 14.0, 14.4, 15.0, 17.5, 18.6, 18.9, 20.9, 21.2, 21.4, 22.1, 22.5, 23.9, 24.2, 24.5, 24.9, 25.6, 26.0, 26.6, 27.2, 27.9, 28.5, 29.3, 30.9, 31.4, 31.8, 32.2, 33.6, 34.3, 35.5, 36.5, 37.3, 37.8 +/- 0.2 two theta values. The crystalline salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane-camphor sulphonic acid having differential scanning calorimetry at 165.78°C
In a broader way, yet another aspect of the invention is the novel crystalline form of intermediate of forumla (II) with N-acetyl-L-glutamic acid for the formation of N-acetyl-L-glutamic acid salt of the intermediate of formula
7

0 0HC/^Y^0HHNYCH30 H2N^/ :U
In a similar way camphor sulfonic acid salt of intermediate (II) of formula

^o
H3C CH3 ^/^Ov

V
o OH

is formed by reacting 4,5-dimethoxy-l-(aminomethyl)benzocyclobutane with camphor sulfonic acid in suitable organic solvent and then recrystallized in a suitable organic solvent to form the novel crystalline form. Novel crystalline form of this acid addition salt by recrystallization in different solvents like alcohol, ketones, esters etc.
An another aspect of the invention is the formation of novel crystalline form of intermediate of formula (III)

MeO
MeO

The present invention provides a crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having X-ray powder diffraction pattern with peaks at 4.6, 9.2, 11.3, 11.9, 12.9, 13.2, 13.9, 14.9, 15.4, 16.1, 16.6, 17.1, 18.6, 19.7, 20.1, 20.5, 21.2, 21.8, 22.5, 23.3, 24.5, 25.7, 26.7, 27.0, 28.1, 28.8, 29.9, 30.2, +/- 0.2 two theta values. A crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having differential scanning calorimeter at 196.32 C
The present invention provides a process for the preparation of crystalline form of 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one having X-ray powder diffraction pattern with peaks at 4.6, 9.2, 11.3, 11.9, 12.9, 13.2, 13.9, 14.9, 15.4, 16.1, 16.6, 17.1, 18.6, 19.7, 20.1, 20.5, 21.2, 21.8, 22.5, 23.3, 24.5, 25.7, 26.7, 27.0, 28.1, 28.8, 29.9, 30.2, +/- 0.2 two theta values, which comprises treating 7,8-dimethoxy-l,2,3,4-tetrahydro-2H-3-benzapin-2-one with alkyl acetate and preferably ethyl acetate.
8

The following examples describes the invention specifically and non-limiting in nature.BRIEF BRIEF DESCRIPTON OF THE ACCOMPANYING DRAWINGS
Fig.I is a characteristic X-ray powder diffraction pattern for Ivabradine Hydrochloride Form-1.
Fig. II is a characteristic differential scanning calorimetry thermogram of Ivabradine Hydrochloride Form-I.
Fig. Ill is a characteristic X-ray powder diffraction pattern for crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt.
Fig. IV is a characteristic differential scanning calorimetry thermogram of crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt.
Fig. V is a characteristic thermal gravimetric analysis of crystalline form of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane N-acetyl-L- gluatamic salt.
Fig. VI is a characteristic X-ray powder diffraction pattern for crystalline form of (lS)-4,5-dimethoxy-1 -(methylaminomethyl)-benzocyclobutane-camphor sulphonate salt.
Fig. VII is a characteristic differential scanning calorimetry thermogram of crystalline form of (1 S)-4,5-dimethoxy-1 -(methylaminomethyl)-benzocyclobutane-camphor sulphonate salt.
Fig. VIII is a characteristic X-ray powder diffraction pattern for crystalline form of 7,8-dimethoxy-1,2,3,4-tetrahydro-2H-3-benzapin-2-one.
Fig. IX is a characteristic differential scanning calorimetry thermogram of crystalline form of 7,8-dimethoxy-l ,2,3,4-tetrahydro-2H-3-benzapin-2-one. WORKING EXAMPLES: 1) Preparation of Ivabradine Base
In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition tunnel with nitrogen gas inlet, 7,8-Dimethoxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one (Intermediate-B) (81.86 g, 0.37 mole) was added followed by the addition of DMSO (160 ml) at room temperature. Further, Potassium-tert-butoxide (47.45 g, 0.42 mole) was added and a clear solution was observed and solid separates out within 5 min. The reaction mixture was stirred for 1 Hr and after stirring for 1 Hr, 3-(Chloro-propyl)-(3,4-dimethoxy-bicyclo[4.2.0]octa-l(6),2,4-trien-7-ylmethyl)-methyl-amine (Intermediate-A,) (110 g, 0.35 mole) was added being dissolved in DMSO (150 ml) within 1 Hr at 25-30 C. The reaction mixture was stirred for 4-5 Hrs at same temperature condition. After completion of the reaction the reaction mass was added to chilled water (1.5 L) and stirred for 15 min. After stirring the layers were
9

separated and the organic layer was dried on sodium sulfate and solvent was completely distilled out to afford the title compound as Ivabradine base.
2) Preparation of Ivabradine Hydrochloride
In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet, Ivabradine Base (lOOg, 0.21 mole) was added followed by the addition of acetonitrile (300 mL) at 20 C. Further, to the reaction mixture IPA HC1 was added drop wise till the pH reaches to 1-2 and the solid was appeared. The reaction mass was cooled to 15-20 C and stirred for 12 Hr at 20 C. After stirring solid was formed and the solid was filtered and washed with acetonitrile under nitrogen atmosphere. Finally, the solid was recrystallized with acetonitrile under reflux condition for 2 Hrs and the solid was filtered and washed with acetonitrile to afford crystalline form of Ivabradine hydrochloride.
3) Preparation of Glutamte salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-
benzocyclobutane
In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet (IS)- 4,5-dimethoxy-l-(methyl amino methyl)-benzocyclobutane (100 g, 0.51 mole) and ethanol (2 L) was added. Further, N-acetyl glutamic acid (98.0 g, 0.51 mole) was added and reaction mass was stirred for 6 Hrs at 80 C. The reaction mass was cooled to 25-30 C and further cooled to 20 C and stirred for 8 Hrs and solid comes out. The solid mass was washed with ethanol (30 mL). The wet solid was crystallized with ethanol (800 mL). The reaction mass was cooled to 15-20 C and stirred for 8 Hrs and again the solid was washed with ethanol (40 mL) and dried in hot air oven for 5 Hrs at 60"C. The solid was again recrystallized with ethanol. To the solid mass water was added and further NaOH solution (230 mL) was added and stirred for 15 min. at 20 C. Further to the reaction mass MDC (370 mL) was added and the layers were separated out. MDC layer was washed with water and dried on sodium sulfate and MDC was distilled out completely under vacuum to afford the title compound as Glutamate salt of (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane.
4) Preparation of Camphor sulphonic acid salt of (lS)-4,5-dimethoxy-l-(methyl
aminomethyl)-benzocyclobutane
In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet (lS)-4,5-dimethoxy-l-(methylaminomethyl)-benzocyclobutane (100 g, 0.48 mole) and (+) Camphor sulphonic acid (500 mL) and IPA (500 mL) was added and refluxed for 6 Hrs. The reaction mixture was slowly cooled
10

to room temperature and stirred for 8 Hrs. After stirring the solid washed with IPA and dried in
oven at 60 C for 6 Hrs. The solid was added into water (5 L) and basified with NaOH till the pH
becomes 12. The reaction was stirred well and extracted with MDC. Finally the solid was dried on
sodium sulfate and MDC was distilled out completely to afford Camphor sulphonic acid salt of
(3,4-dimethoxy-bicyclo[4.2.0]octa-l(6),2,4-trien-7-ylmethyl)methylamine.
5) Preparation of crystalline salt of 7,8-Dimethoxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one
In a 1 liter Round bottom flask equipped with over head stirrer, thermometer pocket with thermometer and addition funnel with nitrogen gas inlet, 7,8-Dimethoxy-2-oxo-l,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (100 g, 0.32 mole) and MDC (350 mL) was added. The reaction mixture was stirred for 15 min. at room temperature. Further the temperature was maintained upto 0-5 C. To the reaction mixture TFA (125 mL) was added drop wise within 2 Hrs at 0-5°C and stirred for 3 Hrs at 0-5°C. To the reaction mixture MDC (2 L) was added and the reaction mass was added into water (500 mL). The layers were separated and to the MDC layer sodium bicarbonate solution (620 mL) was added and again MDC layer was separated out and dried on sodium sulfate and solvent was distilled out completely. Finally to the residue ethyl acetate (250 mL) was added and stirred at 0-5 C for 4 Hrs. The solid was filtered at 0-5 C and finally washed with ethyl acetate to afford the crystalline form of 7,8-Dimethpxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one.
H. StmAMANIAM Of SubramaniantfNataraj & Associates leys for the Applicants
Dated this the 27th day of November 2006
11

Documents:

« Previous Patent

Next Patent »

Patent Number

272755

Indian Patent Application Number

1966/MUM/2006

PG Journal Number

18/2016

Publication Date

29-Apr-2016

Grant Date

25-Apr-2016

Date of Filing

30-Nov-2006

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS RESEARCH CENTRE, ZYDUS TOWER SATELLITE CROSS ROADS, SARKHEJ-GANDHINAGAR HIGHWAY, AHMEDABAD

Inventors:

#	Inventor's Name	Inventor's Address
1	PATEL SUNIL TRIBHOVANDAS	ZYDUS RESEARCH CENTRE, ZYDUS TOWER SATELLITE CROSS ROADS, SARKHEJ-GANDHINAGAR HIGHWAY, AHMEDABAD-380015
2	KUMAR RAJIV	ZYDUS RESEARCH CENTRE, ZYDUS TOWER SATELLITE CROSS ROADS, SARKHEJ-GANDHINAGAR HIGHWAY, AHMEDABAD-380015
3	DWIVEDI SHRIPRAKASH DHAR	ZYDUS RESEARCH CENTRE, ZYDUS TOWER SATELLITE CROSS ROADS, SARKHEJ-GANDHINAGAR HIGHWAY, AHMEDABAD-380015
4	SHAH ALPESHKUMAR PRAVINCHANDRA	CADILA HEALTHCARE LIMITED ZYDUS RESEARCH CENTRE, ZYDUS TOWER SATELLITE CROSS ROADS, SARKHEJ-GANDHINAGAR HIGHWAY, AHMEDABAD-380015,

PCT International Classification Number

C07D223/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA