Indian Patents. 270125:PROCESS FOR THE PREPARATION OF AMORPHOUS IVABRADINE HYDROCHLORIDE

Title of Invention	PROCESS FOR THE PREPARATION OF AMORPHOUS IVABRADINE HYDROCHLORIDE
Abstract	The present invention encompasses a process for the preparation of highly pure amorphous ivabradine hydrochloride by hydrolyzing acid addition salt of ivabradine with a suitable base, and treating ivabradine with alcoholic hydrogen chloride to get highly pure amorphous ivabradine hydrochloride.

Full Text	FIELD OF THE INVENTION The field of the invention relates to the novel processes for the preparation of amorphous ivabradine hydrochloride, an useful antianginal agent. BACKGROUND OF THE INVENTION Ivabradine hydrochloride of formula I, have very valuable pharmacological and therapeutic properties, and are useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino)propyl)-l,3,4,5- tetrahydro-2H-3-benzazepin-2-one hydrochloride. (Formula Removed) Formula I Ivabradine hydrochloride is first disclosed in US patent 5,296,482 and is prepared by hydrogenating benzazepine intermediate of formula II to ivabradine, (Formula Removed) Formula II which is then treated with aqueous hydrochloric acid. Benzazepine intermediate of formula II used for the preparation of ivabradine is prepared by condensing methylamine derivative of formula III, (Formula Removed) Formula III with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV in presence of base in acetone and purified by column chromatography. (Formula Removed) Formula IV However the process suffers from major drawbacks. The chromatographic technique for purification is cumbersome, tedious and difficult to utilize on industrial scale. Use of highly flammable and large quantities of organic solvent in the preparation of benzazepine intermediate of formula II makes this process unattractive for large scale production. It is, therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of highly pure ivabradine or a pharmaceutically acceptable salt where impurity formation is less and hence avoids chromatographic purification and is convenient to operate on a commercial scale. Further, US patent 5,296,482 discloses the process for the preparation of ivabradine only; however the patent is silent about the processes for the preparation of its salts. US patent 7,176,197 reports alpha crystalline form of ivabradine hydrochloride. Several other crystalline forms such as beta, gamma, delta, beta-d, gamma-d and delta-d are also reported by Les Laboratories. There is no data available in the prior art for the existence of amorphous ivabradine hydrochloride although we have disclosed amorphous ivabradine hydrochloride in our pending Indian patent application No. 1157/DEL/2007. Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Phazm Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavai lability pattern may be favoured over another. An amorphous form of cefuroxime axietil is an example of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for cefuroxime axietil pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meets the needs of regulatory agencies and also highly reproducible processes for their preparation. It is, however, possible to provide methods that have successfully and selectively produced ivabradine or a pharmaceutically acceptable salt and ivabradine hydrochloride in amorphous form. SUMMARY OF THE INVENTION One aspect of the present invention is to provide a process for the preparation of amorphous ivabradine hydrochloride which comprises: treating ivabradine with a solution of organic acid in a suitable solvent to get ivabradine acid addition salt, optionally purifying the ivabradine acid addition salt, hydrolysing ivabradine acid addition salt with base in a suitable solvent, treating the resulting ivabradine with alcoholic hydrogen chloride in organic solvent. Another aspect of the present invention is to provide a process for the preparation of amorphous ivabradine hydrochloride which comprises: dissolving ivabradine hydrochloride in a mixture of lower alkanol and ketone at ambient temperature, heating the solution to 40-50°C, distilling the solvent and isolating amorphous ivabradine hydrochloride. Further, another aspect of the present invention is to provide a process for the preparation of amorphous ivabradine hydrochloride which comprises: hydrogenating the benzazepine intermediate of formula II with palladium carbon in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine, (Formula Removed) Formula II treating ivabradine with a solution of organic acid in a suitable solvent to get ivabradine acid addition salt, optionally purifying the ivabradine acid addition salt, hydrolysing ivabradine acid addition salt with aqueous base in a suitable solvent, treating the resulting ivabradine in situ with alcoholic hydrogen chloride in organic solvent. Yet another aspect of the present invention is to provide a process for the preparation of highly pure benzazepine intermediate of formula II, which comprises: condensing methylamine derivative of formula III, (Formula Removed) Formula III with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV, (Formula Removed) Formula IV in presence of a base in water, and further converting benzazepine intermediate of formula II to ivabradine or a pharmaceutically acceptable salt. Ivabradine acid addition salts prepared in the present invention also forms the inventive part of the invention. Ivabradine oxalate is isolated as crystalline solid and is another inventive part of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a powdered X-ray diffraction pattern for amorphous ivabradine hydrochloride. Figure 2 is a DSC thermogram for amorphous ivabradine hydrochloride. Figure 3 is a powdered X-ray diffraction pattern for ivabradine oxalate. Figure 4 is a DSC thermogram for ivabradine oxalate. DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to an efficient and industrially advantageous process for the preparation of highly pure ivabradine or a pharmaceutically acceptable salt and particularly amorphous ivabradine hydrochloride. According to one aspect of the present invention, benzazepine intermediate of formula II is prepared by condensing methylamine derivative of formula III with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV in demineralized water and in presence of base. The condensation reaction is carried out at 45-60°C preferably at 50-55°C and it takes 10-20 hours for completion of reaction. The progress of reaction is monitored by high performance liquid chromatography (HPLC). The product is extracted in lower aliphatic ester solvent such as ethyl acetate. Ethyl acetate layer is further treated with aqueous acidic solution and the resulting layers are separated. The aqueous layer is treated with basic solution and the product is extracted in lower aliphatic ester solvent such as ethyl acetate. Ethyl acetate layer is removed by known methods such as evaporation, distillation with or without vacuum etc to get benzazepine intermediate of formula II. The base is used in the condensation step can be selected from alkali metal carbonates, bicarbonates and hydroxides and preferably potassium carbonate. Major advantages realized in the above process is that the use of water as a solvent, avoiding the use of organic solvents, is to provide an economical, less hazardous and more eco-friendly process to prepare benzazepine intermediate of formula II as compared to the prior art processes. Further the condensation reaction in water produced highly pure benzazepine intermediate of formula II which does not require any further purification and avoid the use of column chromatography. Benzazepine intermediate of formula II prepared is hydrogenated and converted into highly pure ivabradine or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to the preparation of highly pure amorphous ivabradine hydrochloride from ivabradine through ivabradine acid addition salts. Specifically the ivabradine is treated with a solution of organic acid in solvent selected from lower aliphatic ketone such as acetone; ester such as ethyl acetate and nitrile such as acetonitrile to prepare ivabradine acid addition salt. The organic acid can be selected from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic acid, benzenesulphonic acid, toluene sulphonic acid and the like. Preferably the acid is selected from oxalic acid, citric acid, methanesulphonic acid, benzenesulphonic acid, toluene sulphonic acid and most preferably the acid is oxalic acid. Particularly the ivabradine oxalate is prepared by treating ivabradine with oxalic acid in acetone and reaction mass is stirred at ambient temperature for sufficient tine to prepare the oxalate salt. The oxalate salt is isolated by filtration and optionally recrystallized in acetonitrile to isolate pure ivabradine oxalate. The ivabradine oxalate is isolated as crystalline solid and may be characterized by at least one of Karl Fisher or TGA, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC). Crystalline ivabradine oxalate is characterized by powder x-ray diffraction peaks at about 2.04, 2.13, 4.26, 7.06, 8.02, 8.53, 9.32, 10.91, 13.63, 15.07, 16.11, 16.44, 17.48, 18.37, 19.32, 20.38, 20.94, 21.95, 23.61, 24.26, 27.54 and 33.07 degrees two theta, substantially as depicted in Figure 3. Crystalline ivabradine oxalate is further characterized by a differential scanning calorimetry ("DSC") thermogram, which shows one endothermic peak around 110°C due to melting, substantially as depicted in Figure 4. It is advantageous to purify the acid addition salt of ivabradine by known methods such as crystallization or slurring in suitable solvent to remove the unwanted impurities. Preferably, the isolated acid addition salt of ivabradine is recrystallized in a suitable organic solvent such as acetonitrile Acid addition salt of ivabradine is hydrolyzed with a suitable base in demineralized water to get ivabradine. The base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and preferably sodium hydroxide is used. After complete hydrolysis, the desired compound is extracted in organic solvent. The organic solvent can be selected from halogenated hydrocarbon and aliphatic esters and preferably ethyl acetate is used. Ethyl acetate is distilled out to isolate the ivabradine as an oil. Crude ivabradine is further dissolved in a suitable organic solvent such as acetone, ethyl acetate preferably in acetone. The pH of the resulting clear solution is adjusted to 1.0 to 2.0 with alcoholic hydrogen chloride and stirred for 30 to 60 minutes to get highly pure amorphous ivabradine hydrochloride. It is advantageous to dry the organic layer using drying agent such as sodium sulphate or the like before adding alcoholic hydrogen chloride. Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as evaporation, distillation with or without vacuum etc. Optionally the amorphous ivabradine hydrochloride is further stirred for 30 to 60 minutes in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane then filtered and washed with same organic solvent to get amorphous ivabradine hydrochloride. In yet another aspect of the present invention is provided a process for the preparation of amorphous ivabradine hydrochloride by dissolving ivabradine hydrochloride in a mixture of lower alkanol and ketone at ambient temperature and further heated to 40-50°C, distilling out the solvent under vaccum, isolating amorphous ivabradine hydrochloride. The lower alkanol can be selected from methanol, ethanol, propanol, isopropanol and preferably methanol is used. The ketone can be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and preferably acetone is used. Mixture of lower alkanol and ketone is used in a ratio of 1: 2-6 (v/v) more preferably 1:3 (v/v) and most preferably 1:2 (v/v). Specifically ivabradine hydrochloride is dissolved in a mixture of methanol and acetone by simple stirring at room temperature without using prior heating. Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as evaporation, distillation with or without vacuum etc. Alternatively the isolation of highly pure amorphous ivabradine hydrochloride is carried out by stirring the amorphous ivabradine hydrochloride in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane for about 30 to 60 minutes then filtered and washed with same organic solvent to get highly pure amorphous ivabradine hydrochloride. In still yet another aspect of the present invention amorphous ivabradine hydrochloride can also be prepared by catalytically hydrogenating the benzazepine intermediate of formula II using palladium on carbon catalyst in acetic acid under hydrogen pressure of 1-7 kg. The hydrogenation reaction is conducted at ambient temperature and it takes 4-10 hours for completion of reaction, which is monitored by high performance liquid chromatography (HPLC). The catalyst is filtered out and acetic acid is removed by distillation from the filtrate. The residue is taken up in demineralized water and hydrochloric acid, adding a lower aliphatic ester solvent such as ethyl acetate. The layers are separated and aqueous layer is washed with lower aliphatic ester solvent such as ethyl acetate. Aqueous layer is further treated with aqueous sodium hydroxide and the product is extracted in lower aliphatic ester solvent such as ethyl acetate. Multiple extractions are desired to extract the product completely in lower aliphatic ester solvent. Optionally ethyl acetate is distilled out to isolate the ivabradine as an oil, otherwise organic layer of ethyl acetate itself is treated with a solution of organic acid in lower aliphatic ketone such as acetone, ethyl acetate or acetonitrile at 20-30°C for 2-5 hours to prepare ivabradine acid addition salt. If ivabradine is isolated as an oily residue then it is further dissolved in a suitable organic solvent such as acetone, acetonitrile or ethyl acetate and preferably in ethyl acetate before treating it with a solution of organic acid. The organic acid can be selected from the group as given above. Acid addition salt of ivabradine is hydrolyzed with a suitable base in demineralized water to get ivabradine. The base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and preferably sodium hydroxide is used. After complete hydrolysis, the desired compound is extracted in organic solvent. The organic solvent can be selected from halogenated hydrocarbon and aliphatic esters and preferably ethyl acetate is used. Ethyl acetate is distilled out to isolate the ivabradine as oil, which is further dissolved in a suitable organic solvent such as acetone, ethyl acetate preferably in acetone. The pH of the resulting clear solution is adjusted to 1.0 to 2.0 with alcoholic hydrogen chloride and stirred for 30 to 60 minutes to get highly pure amorphous ivabradine hydrochloride. It is advantageous to dry the organic layer of ethyl acetate using drying agent such as sodium sulphate or the like before adding alcoholic hydrogen chloride. The alcohol used in the solution of alcohol-hydrogen chloride is selected from C1-C4 branched or linear aliphatic alcohols and more preferably the solvent is methanol, ethanol, propanol, n-butanol or isopropanol and most preferably the solvent is methanol. In general, a solution of alcohol-hydrogen chloride is prepared by purging dry hydrogen chloride in alcohol by following the methods reported in prior art. The percentage of hydrogen chloride in alcohol is preferably selected between 10-25%. Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as distillation, filtration etc. Optionally the amorphous ivabradine hydrochloride is further stirred for 30 to 60 minutes in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane then filtered and washed with same organic solvent to get highly pure amorphous ivabradine hydrochloride. The precipitated amorphous ivabradine hydrochloride is isolated in high yield and purity of greater than 99.8 % area by HPLC. XRD pattern shows that material is amorphous in nature, substantially as depicted in Figure 1. Amorphous ivabradine hydrochloride is further characterized by a differential scanning calorimetry ("DSC") thermogram, which shows one endothermic peak around 194°C due to melting, substantially as depicted in Figure 2. Amorphous ivabradine hydrochloride is obtained by the described process may have a purity of at least 99.6% area by HPLC, more preferably, of at least 99.7%, and even more preferably, of at least 99.9% area by HPLC. X-ray diffraction of amorphous ivabradine hydrochloride and crystalline ivabradine oxalate are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One of the ordinary skills in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors. DSC analysis was performed using a Mettler Toledo 822 Star6. The crucible was crimped and punched prior to analysis. The weight of the samples was about 4-6 mg; the samples were scanned at a rate of 5°C/min from 30°C to 250°C. The oven was constantly purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 \il aluminum crucibles covered by lids with one hole were used. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the product and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES Example I Preparation of benzazepine intermediate of formula II 7,8-Dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one (38g) and potassium carbonate (60g) were added to a mixture of (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl)amine (20g) and demineralized water (100ml) at room temperature. The reaction mixture was heated and stirred at 50-55°C for 12-16 hrs.. After completion of reaction, reaction mass was cooled to 25-30°C and the product is extracted in ethyl acetate (100ml). The aqueous layer was further extracted with ethyl acetate (60ml). Combined ethyl acetate layers was acidified with aqueous hydrochloric acid and stirred. The layers were separated and pH of the aqueous layer was adjusted to 10.5-12.5 with aqueous sodium hydroxide solution. The aqueous layer is extracted with ethyl acetate (140ml + 60ml). Ethyl acetate was distilled out completely under vacuum to get the title compound. Example 2 Preparation of amorphous ivabradine hydrochloride Benzazepine intermediate of formula II (85g) was taken in acetic acid (700ml), and was hydrogenated under a hydrogen pressure (1-2 kg) at room temperature in the presence of Pd/C (10%, 70g). Further hydrogenation was continued with 6-7 kg hydrogen pressure at 20°C for 6-8 hrs. After completion of hydrogenation (monitored by HPLC), the catalyst was filtered off and acetic acid was removed by distillation. To the residue demineralized water (360ml) and hydrochloric acid (40ml) were added followed by addition of ethyl acetate (200ml). The resulting mixture was stirred and the layers were separated. The aqueous layer was washed with ethyl acetate (100ml). The pH of the aqueous layer was adjusted to 10.5-12.5 with aqueous sodium hydroxide solution and product was extracted in ethyl acetate (400ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out completely. The residue was taken in ethyl acetate (1020ml) and to this oxalic acid (34g) in acetone (68ml) was added slowly and was stirred for 3-4 hours at ambient temperature. The ivabradine oxalate obtained was filtered and recrystallized in acetonitrile. Ivabradine oxalate was taken in demineralized water (340ml) and pH of the reaction mixture was adjusted to 10-12 with aqueous sodium hydroxide solution and stirred. The resulting mixture is then extracted with ethyl acetate (340ml). Ethyl acetate was distilled out completely. Thereafter, the residue was taken in acetone (220ml) and to this methanol-hydrogen chloride (30-35ml) was added slowly and was stirred for 30 minutes. The solvent was removed by distillation under reduced pressure. The amorphous product, thus obtained, was further stirred with n-heptane for 30-40 minutes, filtered, washed with n-heptane (50ml) and dried at 40-45°C to obtain amorphous ivabradine hydrochloride having purity 99.9% area by High performance liquid chromatography (HPLC). XRD pattern showed that product was amorphous in nature and same as depicted in figure 1. Example 3 Preparation of amorphous ivabradine hydrochloride Step-1: Preparation of ivabradine oxalate Ivabradine (44g) was dissolved in ethyl acetate (700ml) and to this oxalic acid (22g) in acetone (50ml) was added slowly and stirred for 3-4 hours at ambient temperature. The ivabradine oxalate, thus obtained was filtered, washed with ethyl acetate (100ml) and recrystallized in acetonitrile (350ml). XRD pattern shows that isolated ivabradine oxalate was crystalline in nature and depicted in Figure 3. Step-2: Preparation of amorphous ivabradine hydrochloride Ivabradine oxalate was taken in demineralized water (200ml) and to this aqueous sodium hydroxide solution (100ml) was added and stirred. The resulting mixture was extracted with ethyl acetate (250ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out completely. The resulting esidue was taken in acetone (100ml) and to this methanol-hydrogen chloride (7ml) was added slowly and was stirred for 30 minutes. Thereafter the solvent was removed by distillation under reduced pressure. To the amorphous product, n-heptane (100ml) was added and stirred for 30 minutes, filtered, washed with n-heptane (50ml) and dried at 40-45°C to obtain the title compound. Example 4 Preparation of amorphous ivabradine hydrochloride Ivabradine hydrochloride (20g) was dissolved in stirred mixture of acetone (100ml) and methanol (50ml) at ambient temperature. The solution was heated to 50°C and the solvent was distilled off under reduced pressure. The amorphous product, thus obtained, was stirred with n-heptane (100ml). The reaction mixture was filtered, washed with n-heptane and dried at 40-45°C under vacuum to obtain the title compound. WE CLAIM 1. A process for the preparation of amorphous ivabradine hydrochloride which comprises: a) treating ivabradine with a solution of organic acid in a suitable solvent to get ivabradine acid addition salt, b) optionally purifying the ivabradine acid addition salt, c) hydrolysing ivabradine acid addition salt with base in a suitable solvent, d) treating the resulting ivabradine with alcoholic hydrogen chloride in organic solvent and e) isolating amorphous ivabradine hydrochloride. 2. The process according to claim 1, wherein the organic acid is selected from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic acid, benzenesulphonic acid, toluene sulphonic acid. 3. The process according to claim 1, wherein the suitable solvent for purifying the ivabradine acid addition salt is acetonitrile. 4. The process according to claim 1, wherein the suitable base for hydrolyzing the ivabradine acid addition salt is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 5. A process for the preparation of amorphous ivabradine hydrochloride which comprises: a) hydrogenating the benzazepine intermediate of formula II with palladium carbon in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine, (Formula Removed) Formula II b) treating ivabradine with a solution of organic acid in a suitable solvent to obtain ivabradine acid addition salt, c) optionally purifying the ivabradine acid addition salt, d) hydrolysing ivabradine acid addition salt with base in a suitable solvent, e) treating the resulting ivabradine in situ with alcoholic hydrogen chloride in organic solvent and f) isolating amorphous ivabradine hydrochloride. 6. The process according to claim 5, wherein the organic acid is selected from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic acid, benzenesulphonic acid, toluene sulphonic acid. 7. The process according to claim 5, wherein the suitable base used for hydrolyzing the ivabradine acid addition salt is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 8. Crystalline ivabradine oxalate having powder x-ray diffraction peaks at about 2.04, 2.13, 4.26, 7.06, 8.02, 8.53, 9.32, 10.91, 13.63, 15.07, 16.11, 16.44, 17.48, 18.37, 19.32, 20.38, 20.94, 21.95, 23.61, 24.26, 27.54 and 33.07 degrees two theta. 9. 9. A process for the preparation of amorphous ivabradine hydrochloride which comprises: dissolving ivabradine hydrochloride in a mixture of lower alkanol and ketone at ambient temperature, heating the solution to 40-50°C, distilling out the solvent and isolating amorphous ivabradine hydrochloride. 10. A process for the preparation of benzazepine intermediate of formula II, (Formula Removed) Formula II comprising: a) condensing methylamine derivative of formula III, (Formula Removed) Formula III with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV, (Formula Removed) Formula IV in demineralized water and in presence of a base to prepare benzazepine intermediate of formula II, converting benzazepine intermediate of formula II to ivabradine or a pharmaceutically acceptable salt.

Full Text

FIELD OF THE INVENTION
The field of the invention relates to the novel processes for the preparation of amorphous ivabradine hydrochloride, an useful antianginal agent.
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride of formula I, have very valuable pharmacological and therapeutic properties, and are useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino)propyl)-l,3,4,5- tetrahydro-2H-3-benzazepin-2-one hydrochloride.
(Formula Removed)
Formula I
Ivabradine hydrochloride is first disclosed in US patent 5,296,482 and is prepared by hydrogenating benzazepine intermediate of formula II to ivabradine,
(Formula Removed)
Formula II
which is then treated with aqueous hydrochloric acid.
Benzazepine intermediate of formula II used for the preparation of ivabradine is
prepared by condensing methylamine derivative of formula III,
(Formula Removed)
Formula III
with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV in presence of base in acetone and purified by column chromatography.
(Formula Removed)
Formula IV
However the process suffers from major drawbacks. The chromatographic technique for purification is cumbersome, tedious and difficult to utilize on industrial scale. Use of highly flammable and large quantities of organic solvent in the preparation of benzazepine intermediate of formula II makes this process unattractive for large scale production.
It is, therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of highly pure ivabradine or a pharmaceutically acceptable salt where impurity formation is less and hence avoids chromatographic purification and is convenient to operate on a commercial scale. Further, US patent 5,296,482 discloses the process for the preparation of ivabradine only; however the patent is silent about the processes for the preparation of its salts.
US patent 7,176,197 reports alpha crystalline form of ivabradine hydrochloride. Several other crystalline forms such as beta, gamma, delta, beta-d, gamma-d and delta-d are also reported by Les Laboratories. There is no data available in the prior art for the existence of amorphous ivabradine hydrochloride although we have disclosed amorphous ivabradine hydrochloride in our pending Indian patent application No. 1157/DEL/2007.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Phazm Bull., 1990; 38: 2003-2007).
For some therapeutic indications, one bioavai lability pattern may be favoured over another. An amorphous form of cefuroxime axietil is an example of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for cefuroxime axietil pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meets the needs of regulatory agencies and also highly reproducible processes for their preparation.
It is, however, possible to provide methods that have successfully and selectively produced ivabradine or a pharmaceutically acceptable salt and ivabradine hydrochloride in amorphous form.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a process for the preparation of
amorphous ivabradine hydrochloride which comprises:
treating ivabradine with a solution of organic acid in a suitable solvent to get
ivabradine acid addition salt,
optionally purifying the ivabradine acid addition salt,
hydrolysing ivabradine acid addition salt with base in a suitable solvent,
treating the resulting ivabradine with alcoholic hydrogen chloride in organic
solvent.
Another aspect of the present invention is to provide a process for the preparation
of amorphous ivabradine hydrochloride which comprises:
dissolving ivabradine hydrochloride in a mixture of lower alkanol and ketone at
ambient temperature,
heating the solution to 40-50°C,
distilling the solvent and
isolating amorphous ivabradine hydrochloride.
Further, another aspect of the present invention is to provide a process for the preparation of amorphous ivabradine hydrochloride which comprises: hydrogenating the benzazepine intermediate of formula II with palladium carbon in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine,
(Formula Removed)
Formula II
treating ivabradine with a solution of organic acid in a suitable solvent to get
ivabradine acid addition salt,
optionally purifying the ivabradine acid addition salt,
hydrolysing ivabradine acid addition salt with aqueous base in a suitable solvent,
treating the resulting ivabradine in situ with alcoholic hydrogen chloride in
organic solvent.
Yet another aspect of the present invention is to provide a process for the
preparation of highly pure benzazepine intermediate of formula II, which
comprises:
condensing methylamine derivative of formula III,
(Formula Removed)
Formula III
with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV,
(Formula Removed)
Formula IV
in presence of a base in water,
and further converting benzazepine intermediate of formula II to ivabradine or a
pharmaceutically acceptable salt.
Ivabradine acid addition salts prepared in the present invention also forms the inventive part of the invention. Ivabradine oxalate is isolated as crystalline solid and is another inventive part of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a powdered X-ray diffraction pattern for amorphous ivabradine
hydrochloride.
Figure 2 is a DSC thermogram for amorphous ivabradine hydrochloride.
Figure 3 is a powdered X-ray diffraction pattern for ivabradine oxalate.
Figure 4 is a DSC thermogram for ivabradine oxalate.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to an efficient and industrially advantageous process for the preparation of highly pure ivabradine or a pharmaceutically acceptable salt and particularly amorphous ivabradine hydrochloride.
According to one aspect of the present invention, benzazepine intermediate of formula II is prepared by condensing methylamine derivative of formula III with
7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV in demineralized water and in presence of base.
The condensation reaction is carried out at 45-60°C preferably at 50-55°C and it takes 10-20 hours for completion of reaction. The progress of reaction is monitored by high performance liquid chromatography (HPLC). The product is extracted in lower aliphatic ester solvent such as ethyl acetate. Ethyl acetate layer is further treated with aqueous acidic solution and the resulting layers are separated. The aqueous layer is treated with basic solution and the product is extracted in lower aliphatic ester solvent such as ethyl acetate. Ethyl acetate layer is removed by known methods such as evaporation, distillation with or without vacuum etc to get benzazepine intermediate of formula II.
The base is used in the condensation step can be selected from alkali metal carbonates, bicarbonates and hydroxides and preferably potassium carbonate.
Major advantages realized in the above process is that the use of water as a solvent, avoiding the use of organic solvents, is to provide an economical, less hazardous and more eco-friendly process to prepare benzazepine intermediate of formula II as compared to the prior art processes. Further the condensation reaction in water produced highly pure benzazepine intermediate of formula II which does not require any further purification and avoid the use of column chromatography.
Benzazepine intermediate of formula II prepared is hydrogenated and converted into highly pure ivabradine or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention relates to the preparation of highly pure amorphous ivabradine hydrochloride from ivabradine through ivabradine acid addition salts. Specifically the ivabradine is treated with a solution of organic acid in solvent selected from lower aliphatic ketone such as acetone; ester such as ethyl acetate and nitrile such as acetonitrile to prepare ivabradine acid addition salt.
The organic acid can be selected from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic acid, benzenesulphonic acid, toluene sulphonic acid and the like. Preferably the acid is selected from oxalic acid, citric acid, methanesulphonic acid, benzenesulphonic acid, toluene sulphonic acid and most preferably the acid is oxalic acid.
Particularly the ivabradine oxalate is prepared by treating ivabradine with oxalic acid in acetone and reaction mass is stirred at ambient temperature for sufficient tine to prepare the oxalate salt. The oxalate salt is isolated by filtration and optionally recrystallized in acetonitrile to isolate pure ivabradine oxalate. The ivabradine oxalate is isolated as crystalline solid and may be characterized by at least one of Karl Fisher or TGA, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC).
Crystalline ivabradine oxalate is characterized by powder x-ray diffraction peaks at about 2.04, 2.13, 4.26, 7.06, 8.02, 8.53, 9.32, 10.91, 13.63, 15.07, 16.11, 16.44, 17.48, 18.37, 19.32, 20.38, 20.94, 21.95, 23.61, 24.26, 27.54 and 33.07 degrees two theta, substantially as depicted in Figure 3.
Crystalline ivabradine oxalate is further characterized by a differential scanning calorimetry ("DSC") thermogram, which shows one endothermic peak around 110°C due to melting, substantially as depicted in Figure 4.
It is advantageous to purify the acid addition salt of ivabradine by known methods such as crystallization or slurring in suitable solvent to remove the unwanted impurities. Preferably, the isolated acid addition salt of ivabradine is recrystallized in a suitable organic solvent such as acetonitrile
Acid addition salt of ivabradine is hydrolyzed with a suitable base in demineralized water to get ivabradine.
The base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and preferably sodium hydroxide is used. After complete hydrolysis, the desired compound is extracted in organic solvent. The organic solvent can be selected from halogenated hydrocarbon and aliphatic esters and preferably ethyl acetate is used. Ethyl acetate is distilled out to isolate the ivabradine as an oil. Crude ivabradine is further dissolved in a suitable organic solvent such as acetone, ethyl acetate preferably in acetone. The pH of the resulting clear solution is adjusted to 1.0 to 2.0 with alcoholic hydrogen chloride and stirred for 30 to 60 minutes to get highly pure amorphous ivabradine hydrochloride. It is advantageous to dry the organic layer using drying agent such as sodium sulphate or the like before adding alcoholic hydrogen chloride.
Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as evaporation, distillation with or without vacuum etc.
Optionally the amorphous ivabradine hydrochloride is further stirred for 30 to 60 minutes in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane then filtered and washed with same organic solvent to get amorphous ivabradine hydrochloride.
In yet another aspect of the present invention is provided a process for the preparation of amorphous ivabradine hydrochloride by dissolving ivabradine hydrochloride in a mixture of lower alkanol and ketone at ambient temperature and further heated to 40-50°C, distilling out the solvent under vaccum, isolating amorphous ivabradine hydrochloride.
The lower alkanol can be selected from methanol, ethanol, propanol, isopropanol and preferably methanol is used. The ketone can be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and preferably acetone is used. Mixture of lower alkanol and ketone is used in a ratio of 1: 2-6 (v/v) more preferably 1:3 (v/v) and most preferably 1:2 (v/v).
Specifically ivabradine hydrochloride is dissolved in a mixture of methanol and acetone by simple stirring at room temperature without using prior heating.
Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as evaporation, distillation with or without vacuum etc.
Alternatively the isolation of highly pure amorphous ivabradine hydrochloride is carried out by stirring the amorphous ivabradine hydrochloride in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane for about 30 to 60 minutes then filtered and washed with same organic solvent to get highly pure amorphous ivabradine hydrochloride.
In still yet another aspect of the present invention amorphous ivabradine hydrochloride can also be prepared by catalytically hydrogenating the benzazepine intermediate of formula II using palladium on carbon catalyst in acetic acid under hydrogen pressure of 1-7 kg. The hydrogenation reaction is conducted at ambient temperature and it takes 4-10 hours for completion of reaction, which is monitored by high performance liquid chromatography (HPLC). The catalyst is filtered out and acetic acid is removed by distillation from the filtrate. The residue is taken up in demineralized water and hydrochloric acid, adding a lower aliphatic ester solvent such as ethyl acetate. The layers are separated and aqueous layer is washed with lower aliphatic ester solvent such as ethyl acetate. Aqueous layer is further treated with aqueous sodium hydroxide and the product is extracted in lower aliphatic ester solvent such as ethyl acetate.
Multiple extractions are desired to extract the product completely in lower aliphatic ester solvent.
Optionally ethyl acetate is distilled out to isolate the ivabradine as an oil, otherwise organic layer of ethyl acetate itself is treated with a solution of organic acid in lower aliphatic ketone such as acetone, ethyl acetate or acetonitrile at 20-30°C for 2-5 hours to prepare ivabradine acid addition salt.
If ivabradine is isolated as an oily residue then it is further dissolved in a suitable organic solvent such as acetone, acetonitrile or ethyl acetate and preferably in ethyl acetate before treating it with a solution of organic acid. The organic acid can be selected from the group as given above.
Acid addition salt of ivabradine is hydrolyzed with a suitable base in demineralized water to get ivabradine.
The base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and preferably sodium hydroxide is used.
After complete hydrolysis, the desired compound is extracted in organic solvent. The organic solvent can be selected from halogenated hydrocarbon and aliphatic esters and preferably ethyl acetate is used. Ethyl acetate is distilled out to isolate the ivabradine as oil, which is further dissolved in a suitable organic solvent such as acetone, ethyl acetate preferably in acetone. The pH of the resulting clear solution is adjusted to 1.0 to 2.0 with alcoholic hydrogen chloride and stirred for 30 to 60 minutes to get highly pure amorphous ivabradine hydrochloride. It is advantageous to dry the organic layer of ethyl acetate using drying agent such as sodium sulphate or the like before adding alcoholic hydrogen chloride.
The alcohol used in the solution of alcohol-hydrogen chloride is selected from C1-C4 branched or linear aliphatic alcohols and more preferably the solvent is methanol, ethanol, propanol, n-butanol or isopropanol and most preferably the
solvent is methanol. In general, a solution of alcohol-hydrogen chloride is prepared by purging dry hydrogen chloride in alcohol by following the methods reported in prior art. The percentage of hydrogen chloride in alcohol is preferably selected between 10-25%.
Amorphous ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by known methods such as distillation, filtration etc.
Optionally the amorphous ivabradine hydrochloride is further stirred for 30 to 60 minutes in a suitable organic solvent such as n-heptane, n-hexane and cyclohexane then filtered and washed with same organic solvent to get highly pure amorphous ivabradine hydrochloride.
The precipitated amorphous ivabradine hydrochloride is isolated in high yield and purity of greater than 99.8 % area by HPLC. XRD pattern shows that material is amorphous in nature, substantially as depicted in Figure 1.
Amorphous ivabradine hydrochloride is further characterized by a differential scanning calorimetry ("DSC") thermogram, which shows one endothermic peak around 194°C due to melting, substantially as depicted in Figure 2.
Amorphous ivabradine hydrochloride is obtained by the described process may have a purity of at least 99.6% area by HPLC, more preferably, of at least 99.7%, and even more preferably, of at least 99.9% area by HPLC.
X-ray diffraction of amorphous ivabradine hydrochloride and crystalline ivabradine oxalate are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One of the ordinary skills in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors.
DSC analysis was performed using a Mettler Toledo 822 Star6. The crucible was crimped and punched prior to analysis. The weight of the samples was about 4-6 mg; the samples were scanned at a rate of 5°C/min from 30°C to 250°C. The oven was constantly purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 \il aluminum crucibles covered by lids with one hole were used.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the product and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example I
Preparation of benzazepine intermediate of formula II
7,8-Dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one (38g) and potassium carbonate (60g) were added to a mixture of (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl)amine (20g) and demineralized water (100ml) at room temperature. The reaction mixture was heated and stirred at 50-55°C for 12-16 hrs.. After completion of reaction, reaction mass was cooled to 25-30°C and the product is extracted in ethyl acetate (100ml). The aqueous layer was further extracted with ethyl acetate (60ml). Combined ethyl acetate layers was acidified with aqueous hydrochloric acid and stirred. The layers were separated and pH of the aqueous layer was adjusted to 10.5-12.5 with aqueous sodium hydroxide solution. The aqueous layer is extracted with ethyl acetate (140ml + 60ml). Ethyl acetate was distilled out completely under vacuum to get the title compound.
Example 2
Preparation of amorphous ivabradine hydrochloride
Benzazepine intermediate of formula II (85g) was taken in acetic acid (700ml), and was hydrogenated under a hydrogen pressure (1-2 kg) at room temperature in the presence of Pd/C (10%, 70g). Further hydrogenation was continued with 6-7 kg hydrogen pressure at 20°C for 6-8 hrs. After completion of hydrogenation (monitored by HPLC), the catalyst was filtered off and acetic acid was removed by distillation. To the residue demineralized water (360ml) and hydrochloric acid (40ml) were added followed by addition of ethyl acetate (200ml). The resulting mixture was stirred and the layers were separated. The aqueous layer was washed with ethyl acetate (100ml). The pH of the aqueous layer was adjusted to 10.5-12.5 with aqueous sodium hydroxide solution and product was extracted in ethyl acetate (400ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out completely. The residue was taken in ethyl acetate (1020ml) and to this oxalic acid (34g) in acetone (68ml) was added slowly and was stirred for 3-4 hours at ambient temperature. The ivabradine oxalate obtained was filtered and recrystallized in acetonitrile. Ivabradine oxalate was taken in demineralized water (340ml) and pH of the reaction mixture was adjusted to 10-12 with aqueous sodium hydroxide solution and stirred. The resulting mixture is then extracted with ethyl acetate (340ml). Ethyl acetate was distilled out completely. Thereafter, the residue was taken in acetone (220ml) and to this methanol-hydrogen chloride (30-35ml) was added slowly and was stirred for 30 minutes. The solvent was removed by distillation under reduced pressure. The amorphous product, thus obtained, was further stirred with n-heptane for 30-40 minutes, filtered, washed with n-heptane (50ml) and dried at 40-45°C to obtain amorphous ivabradine hydrochloride having purity 99.9% area by High performance liquid chromatography (HPLC). XRD pattern showed that product was amorphous in nature and same as depicted in figure 1.
Example 3
Preparation of amorphous ivabradine hydrochloride
Step-1: Preparation of ivabradine oxalate
Ivabradine (44g) was dissolved in ethyl acetate (700ml) and to this oxalic acid (22g) in acetone (50ml) was added slowly and stirred for 3-4 hours at ambient temperature. The ivabradine oxalate, thus obtained was filtered, washed with ethyl acetate (100ml) and recrystallized in acetonitrile (350ml). XRD pattern shows that isolated ivabradine oxalate was crystalline in nature and depicted in Figure 3.
Step-2: Preparation of amorphous ivabradine hydrochloride
Ivabradine oxalate was taken in demineralized water (200ml) and to this aqueous sodium hydroxide solution (100ml) was added and stirred. The resulting mixture was extracted with ethyl acetate (250ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out completely. The resulting esidue was taken in acetone (100ml) and to this methanol-hydrogen chloride (7ml) was added slowly and was stirred for 30 minutes. Thereafter the solvent was removed by distillation under reduced pressure. To the amorphous product, n-heptane (100ml) was added and stirred for 30 minutes, filtered, washed with n-heptane (50ml) and dried at 40-45°C to obtain the title compound.
Example 4
Preparation of amorphous ivabradine hydrochloride
Ivabradine hydrochloride (20g) was dissolved in stirred mixture of acetone (100ml) and methanol (50ml) at ambient temperature. The solution was heated to 50°C and the solvent was distilled off under reduced pressure. The amorphous product, thus obtained, was stirred with n-heptane (100ml). The reaction mixture was filtered, washed with n-heptane and dried at 40-45°C under vacuum to obtain the title compound.

WE CLAIM
1. A process for the preparation of amorphous ivabradine hydrochloride
which comprises:
a) treating ivabradine with a solution of organic acid in a suitable
solvent to get ivabradine acid addition salt,
b) optionally purifying the ivabradine acid addition salt,
c) hydrolysing ivabradine acid addition salt with base in a suitable
solvent,
d) treating the resulting ivabradine with alcoholic hydrogen chloride
in organic solvent and
e) isolating amorphous ivabradine hydrochloride.

2. The process according to claim 1, wherein the organic acid is selected
from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid,
oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic
acid, benzenesulphonic acid, toluene sulphonic acid.
3. The process according to claim 1, wherein the suitable solvent for
purifying the ivabradine acid addition salt is acetonitrile.
4. The process according to claim 1, wherein the suitable base for
hydrolyzing the ivabradine acid addition salt is selected from sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium bicarbonate and potassium bicarbonate.
5. A process for the preparation of amorphous ivabradine hydrochloride
which comprises:
a) hydrogenating the benzazepine intermediate of formula II with palladium carbon in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine,
(Formula Removed)
Formula II
b) treating ivabradine with a solution of organic acid in a suitable
solvent to obtain ivabradine acid addition salt,
c) optionally purifying the ivabradine acid addition salt,
d) hydrolysing ivabradine acid addition salt with base in a suitable
solvent,
e) treating the resulting ivabradine in situ with alcoholic hydrogen
chloride in organic solvent and
f) isolating amorphous ivabradine hydrochloride.

6. The process according to claim 5, wherein the organic acid is selected
from acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid,
oxalic acid, citric acid, benzoic acid, methanesulphonic acid, isethionic
acid, benzenesulphonic acid, toluene sulphonic acid.
7. The process according to claim 5, wherein the suitable base used for
hydrolyzing the ivabradine acid addition salt is selected from sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium bicarbonate and potassium bicarbonate.
8. Crystalline ivabradine oxalate having powder x-ray diffraction peaks at
about 2.04, 2.13, 4.26, 7.06, 8.02, 8.53, 9.32, 10.91, 13.63, 15.07, 16.11,
16.44, 17.48, 18.37, 19.32, 20.38, 20.94, 21.95, 23.61, 24.26, 27.54 and
33.07 degrees two theta.
9. 9. A process for the preparation of amorphous ivabradine hydrochloride
which comprises:
dissolving ivabradine hydrochloride in a mixture of lower alkanol and
ketone at ambient temperature,
heating the solution to 40-50°C,
distilling out the solvent and
isolating amorphous ivabradine hydrochloride.
10. A process for the preparation of benzazepine intermediate of formula II,
(Formula Removed)
Formula II
comprising: a) condensing methylamine derivative of formula III,
(Formula Removed)
Formula III
with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula IV,
(Formula Removed)
Formula IV
in demineralized water and in presence of a base to prepare benzazepine intermediate of formula II,
converting benzazepine intermediate of formula II to ivabradine or a pharmaceutically acceptable salt.

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Patent Number

270125

Indian Patent Application Number

1950/DEL/2007

PG Journal Number

49/2015

Publication Date

04-Dec-2015

Grant Date

29-Nov-2015

Date of Filing

13-Sep-2007

Name of Patentee

IND-SWIFT LABORATORIES LIMITED

Applicant Address

S.C.O. NO.850, SHIVALIK ENCLAVE, NAC MANIMAJRA,CHANDIGARH-160 101 INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SATYENDRA PAL SINGH	405, MANSA DEVI COMPLEX,GH-12, SECTOR 5, PANCHKULA-(HARYANA)
2	SINGH GAJENDRA	304, GH-19, SECTOR 20,PANCHKULA-(HARYANA)
3	WADHWA LALIT	408, SHAKTI APARTMENTS, SECTOR 14, PANCHKULA-(HARYANA)

PCT International Classification Number

C07D223/16

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA