WO2014102827A1 - Procédé de préparation d'ivabradine - Google Patents

Procédé de préparation d'ivabradine Download PDF

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Publication number
WO2014102827A1
WO2014102827A1 PCT/IN2013/000809 IN2013000809W WO2014102827A1 WO 2014102827 A1 WO2014102827 A1 WO 2014102827A1 IN 2013000809 W IN2013000809 W IN 2013000809W WO 2014102827 A1 WO2014102827 A1 WO 2014102827A1
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Prior art keywords
ivabradine
compound
reaction mixture
formula iii
borate
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PCT/IN2013/000809
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English (en)
Inventor
Shekhar Bhaskar Bhirud
Kumar Hari Bhushan
Sunil Sudhakar Zope
Dipak Vinayak PATIL
Pramod Amrutrao DHEBADE
Prem Chand
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Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
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Application filed by Glenmark Pharmaceuticals Limited; Glenmark Generics Limited filed Critical Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
Publication of WO2014102827A1 publication Critical patent/WO2014102827A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a process for the preparation of ivabradine and pharmaceutically acceptable salts thereof.
  • the present invention relates to a process for the preparation of amorphous form of ivabradine hydrochloride.
  • Ivabradine also known as (5)-7,8-Dimethoxy-3- ⁇ 3- ⁇ N-[(4,5- dimethoxybenzocyclobut- 1 -yl)methyl]-V-(methyl)amino ⁇ propyl ⁇ - 1 ,3 ,4,5-tetrahydro-2H- 3-benzazepin-2-on I
  • Ivabradine hydrochloride a compound of formula II, is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. It is also indicated for the treatment of stable chronic heart failure (NHYA II-IV). II
  • United States Patent No. 5296482 discloses ivabradine and its salts.
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride.
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising: (a) dissolving a crystalline ivabradine hydrochloride in a solvent or mixture of solvents or ' aqueous mixtures thereof to provide a solution; and
  • the present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by high performance liquid chromatography.
  • the present invention provides borate salt of compound of formula III.
  • the present invention provides a process for the preparation of amorphous ivabradine hydrochloride, the process comprising:
  • the present invention provides ivabradine borate characterized by an X-ray powder diffraction pattern, which is substantially , in accordance with Figure 1 ; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 2; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 3; a Fourier transform infrared spectrum, which is substantially in accordance with Figure 4; a 13 C nuclear magnetic resonance spectrum, which is in accordance with Figure 5; and a combination thereof.
  • the present invention provides ivabradine borate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ at about 5.63, 10.12, 14.21, 19.12, 19.67, 22.16.
  • the present invention provides a process for the preparation of ivabradine borate, the process comprising:
  • the present invention provides use of ivabradine borate in the preparation of ivabradine hydrochloride.
  • Figure 1 is a characteristic XRPD of ivabradine borate as obtained in Example 15.
  • Figure 2 is a DSC thermogram of ivabradine borate as obtained in Example 15.
  • Figure 3 is a TGA thermogram of ivabradine borate as obtained in Example 15.
  • Figure 4 is an IR spectrum of ivabradine borate as obtained in Example 15.
  • Figure 5 is a 13 C NMR spectrum of ivabradine borate as obtained in Example 15. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
  • room temperature means a temperature of about 25°C to about 30°C.
  • a crystalline ivabradine hydrochloride is dissolved in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution.
  • the solvent used for dissolution of crystalline ivabradine hydrochloride includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride,
  • Stirring may be continued for any desired time period to achieve a complete dissolution of the compound.
  • the stirring time may range from about 30 minutes to about 3 hours, or longer.
  • the solution may be optionally treated with charcoal and filtered to get a particle-free solution.
  • the solvent is removed from the solution obtained in (a).
  • Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated by lyophilization, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
  • solvent was removed by lyophilization to give amorphous form of ivabradine hydrochloride.
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
  • the solvent may be selected from the solvents as discussed supra and the removal of solvent may be carried out as discussed supra.
  • the solvent is water.
  • the solvent removal is by lyophilization.
  • Lyophilization is typically done by a process comprising cooling the solution to obtain a cooled mixture, and evaporating the solvent while maintaining the mixture cooled at low temperatures.
  • the solution is cooled to a temperature of about -
  • the lyophilizing step may be done under vacuum (not less than about lOOmillitorr).
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising: (a) dissolving a crystalline form of ivabradine hydrochloride, having XRPD peaks below, in a solvent or mixture of solvents or aqueous mixtures thereof to provide solution; and
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
  • the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, wherein the amorphous form of ivabradine hydrochloride obtained has compounds of formula A, III or IVa present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by hig A
  • the present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, as determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, preferably less than 0.05% w/w, more preferably absent, as determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
  • Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
  • the retention time of ivabradine hydrochloride is about 37.0 minutes under these conditions.
  • Relative retention time for compound of formula IV is about 0.19, for compound of formula III is about 1.14, for compound of formula A is about 1.17 with respect to ivabradine hydrochloride.
  • the present invention provides a process for the preparation of crystalline ivabradine hydrochloride, the process comprising:
  • a compound of formula IV or salt thereof is condensed with a compound of formula V, wherein X is selected from the group consisting of CI, Br, I, to give a compound of formula III.
  • the compound of formula IV or alt thereof is condensed with the compound of formula V, wherein X is I, to give the compound of formula III.
  • the reaction may be carried out in the presence of a suitable base.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n
  • the reaction may be carried ⁇ in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene -and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is dimethyl formamide.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 80°C.
  • the reaction is carried out for a period of about 3 hours to about 20 hours.
  • Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 5 hours to about 16 hours.
  • the compound of formula IV or salt thereof is condensed with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one, a compound of formula Va,
  • the compound of formula IV or salt thereof is condensed with the compound of formula Va, in the presence of potassium carbonate in dimethyl formamide.
  • the compound of formula III is not isolated from the reaction mixture.
  • the compound of formula Va is obtained by converting 7,8-dimethoxy-3-[3- chloropropyl]- l,3-dihydro-2H-3-benzazepin-2-one, a compound of formula Vb,
  • the metal iodide includes, but is not limited to alkali metal iodide such as sodium iodide, potassium iodide and the like.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; acetonitrile; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like
  • ethers such as dimethyl ether, dieth
  • the solvent selected is acetone, methyl ethyl ketone.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 100°C. The reaction is carried out for a period of about 5 hours to about 40 hours. Preferably the reaction is carried out at a temperature of about 50°C to about 80°C for a period of about 5 hours to about 15 hours.
  • the compound of formula V, wherein X is CI is converted to a compound of formula V, wherein X is I, in methyl ethyl ketone.
  • the compound of formula V is obtained by condensing 7,8-dimethoxy- l ,3- dihydro-2H-3-benzazepin-2-one, a compound of formula VI, VI
  • X is selected from the group consisting of CI, Br, I,
  • the compound of formula Vb is obtained by condensing 7,8-dimethoxy- l ,3- dihydro-2H-3-benzazepin-2-one, a compound of formula VI,
  • the reaction may be carried out in the presence of a suitable base.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is dimethyl sulfoxide.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 60°C.
  • the reaction is carried out for a period of about 2 hours to about 8 hours.
  • Preferably the reaction is carried out at a temperature of about 20°C to about 35°C for a period of about 2 hours to about 5 hours.
  • the reducing agent is selected from the group consisting of sodium dithionite, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition .
  • metal borohydride/alkaline earth metal halide alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, transition metal borohydride/transition metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction using hydrogen transfer reagent such as ammonium formate, sodium formate, trialkyl ammonium formates, formic acid, phosphoric acid, hydrazine, monosodium dihydrogen orthophosphate, cyclohexene, cyclohexadiene, hydrazinium monoformate in the presence of magnesium powder, or reduction by catalytic hydrogenation using hydrogenation catalyst including, but not limited to palladium on carbon, palladium hydroxide, platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, Raney nickel, zinc dust.
  • the compound of formula III is reduced to ivabradine by cata
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is methanol, ethyl acetate.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 1 10°C.
  • the reaction is carried out for a period of about 5 hours to about 30 hours.
  • Preferably the reaction is carried out at a temperature of about 50°C to about 80°C for a period of about 8 hours to about 20 hours.
  • ivabradine is treated with alcoholic hydrochloric acid to obtain ivabradine hydrochloride.
  • the alcohol containing hydrochloric acid is selected from ethanol, methanol, n- propyl alcohol, isopropyl alcohol, butanol and the like; or mixtures thereof.
  • the alcohol selected is isopropyl alcohol.
  • the reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof.
  • suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; halo
  • the reaction may be carried out at a temperature in the range of about 0°C to about 85°C for a period of about 2 hours to about 10 hours.
  • the reaction is carried out at a temperature of about 0°C to about 50°C for a period of about 2 hours to about 6 hours.
  • the ivabradine hydrochloride is recrystallized from alcohol or nitrile or mixtures thereof.
  • the ivabradine hydrochloride may be recrystallized by addition of alcohol which ⁇ includes, but is not limited to ethanol, methanol, propanol, butanol and the like; nitrile which includes, but is not limited to acetonitrile; or mixtures thereof.
  • alcohol which ⁇ includes, but is not limited to ethanol, methanol, propanol, butanol and the like
  • nitrile which includes, but is not limited to acetonitrile
  • the ivabradine hydrochloride is recrystallized from methanol-acetonitrile mixture.
  • the crystalline ivabradine hydrochloride obtained is a polymorph mixture of ⁇ -crystalline form and 5d-crystalline form of ivabradine hydrochloride.
  • the present invention provides the compound of formula III in a purity of at least 95%, preferably at least 99%, as determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the present invention provides a process for the preparation of the compound of formula III in a purity of at least 95%, as determined by high performance liquid chromatography, by a process comprising:
  • the suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the acid is boric acid.
  • the reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is acetonitrile.
  • the reaction may be carried out at a temperature in the range of about 0°C to about the reflux temperature of the solvent for a period of about 2 hours to about 20 hours.
  • the reaction is carried out at a temperature of about 40°C to about 90°C for a period of about 2 hours to about 10 hours.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; a source of ammonia such as ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia.
  • the base selected is aqueous ammonia.
  • the method may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like or extraction in an organic solvent followed, removal of solvent. Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum.
  • the present invention provides a process for the preparation of the compound of formula III in a purity of at least 99%, as determined by high performance liquid chromatography, by a process comprising:
  • the present invention provides borate salt of compound of formula III.
  • the present invention provides ivabradine borate.
  • the present invention provides ivabradine borate characterized by an X-ray powder diffraction pattern, which is substantially in accordance with Figure 1 ; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 2; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 3; a Fourier transform infrared spectrum, which is substantially in accordance with Figure 4; a 13 C nuclear magnetic resonance spectrum, which is in accordance with Figure 5; and a combination thereof.
  • the present invention provides ivabradine borate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ at about 5.63, 10.12, 14.21 , 19.12, 19.67, 22.16.
  • the present invention provides a process for the preparation of ivabradine borate, the process comprising:
  • the reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is acetonitrile.
  • the reaction may be carried out at a temperature in the range of about 0°C to about the reflux temperature of the solvent for a period of about 2 hours to about 20 hours.
  • the reaction is carried out at a temperature of about 40°C to about 90°C for a period of about 2 hours to about 10 hours.
  • the ivabradine borate obtained is isolated by any method known in the art.
  • the method may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
  • the ivabradine borate salt may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent is acetonitrile-methanol mixture.
  • Suitable temperatures for dissolution of ivabradine borate salt in a solvent may range from about 40°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 2 hours to about 20 hours.
  • the product is isolated by conventional methods known in the art, preferably, filtration.
  • the ivabradine borate salt may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.
  • the present invention provides ivabradine borate, obtained by the above process, as characterized and analyzed by following techniques:
  • the samples were scanned in the full 2 ⁇ range of 2-50° with a "time-per-step" optimized to 50 sec.
  • the present invention provides a process for the preparation of amorphous ivabradine hydrochloride, the process comprising:
  • ivabradine borate is reacted with a base to form ivabradine.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; a source of ammonia such as ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia.
  • the base selected is aqueous ammonia.
  • ivabradine is treated with hydrochloric acid to form a reaction mixture.
  • the hydrochloric acid may be in an aqueous, anhydrous or gaseous form.
  • aqueous hydrochloric acid or solvent containing hydrogen chloride or gas containing hydrogen chloride may be used.
  • aqueous hydrochloric acid is used.
  • Suitable temperature for addition of hydrochloric acid may range from about 0°C to about 85°C.
  • addition of hydrochloric acid is carried at about 15°C to about 35°C.
  • the solution may be optionally treated with charcoal and filtered to get a particle- free solution.
  • Isolation of amorphous ivabradine hydrochloride may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by solvent distillation, lyophilization, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
  • solvent was removed lyophilization to give amorphous form of ivabradine hydrochloride.
  • the present invention provides use of ivabradine borate in the preparation of ⁇ ivabradine hydrochloride. [0103] In one embodiment, the present invention provides use of ivabradine borate in the preparation of ivabradine hydrochloride, wherein ivabradine hydrochloride is in amorphous form.
  • the present invention provides a process for the preparation of ivabradine, a compound of for I
  • a suitable hydrogen transfer reagent is selected from the group consisting of ammonium formate, sodium formate, trialkyl ammonium formates, formic acid, phosphoric acid, hydrazine, monosodium dihydrogen orthophosphate, cyclohexene, cyclohexadiene, hydrazinium mono formate in the presence , of magnesium powder.
  • the hydrogen transfer reagent selected is ammonium formate.
  • the reaction may be carried out in the presence of a hydrogenation catalyst.
  • a suitable hydrogenation catalyst includes, but is not limited to palladium on carbon, palladium hydroxide, platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, Raney nickel, zinc dust.
  • the hydrogenation catalyst selected is palladium on carbon.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1 -butanol, 2-butanol, 1 -pentanol, l ⁇ -octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
  • the solvent selected is methanol.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 1 10°C.
  • the reaction is carried out for a period of about 10 hours to about 30 hours.
  • Preferably the reaction is carried out at a temperature of about 50°C to about 65°C for a period of about 12 hours to about 20 hours.
  • the present invention provides a process for the preparation of ivabradine, the process comprising reducing (5)-7,8-dimethoxy-3- ⁇ 3- ⁇ N-[(4,5- dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino ⁇ propyl ⁇ - l ,3-dihydro-2H-3- benzazepin-2-one, a compound of formula III using ammonium formate and palladium on carbon in methanol to give ivabradine, the compound of formula I.
  • the ivabradine acid addition salts may be prepared by reacting ivabradine with a pharmaceutically acceptable acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid.
  • a pharmaceutically acceptable acid such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the acid is hydrochloric acid.
  • a solvent containing an acid can be used.
  • the suitable solvent containing an acid includes esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, n-propyl alcohol, isopropyl alcohol, butanol and the like; ketones " such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof.
  • the solvent selected is isopropyl alcohol.
  • the reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof.
  • suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; halo
  • the ivabradine acid-addition salt formation may be carried out at a temperature in the range of about 0°C to about 85°C for a period of about 2 hours to about 10 hours.
  • the reaction is carried out at a temperature of about 0°C to about 56°C for a period of about 2 hours to about 6 hours.
  • the ivabradine acid-addition salts may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; acetonitrile; water or mixtures thereof.
  • the solvent is acetonitrile.
  • Suitable temperatures for dissolution of ivabradine acid-addition salts in a solvent may range from about 40°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 2 hours to about 6 hours.
  • the product is isolated by conventional methods known in the art, preferably, filtration.
  • the reaction mixture was cooled, quenched into chilled water and stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was acidified to pH of about 3 to about 4 using hydrochloric acid and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the aqueous layer was basified to pH of about 8 to about 9 using aqueous ammonia and toluene was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the organic layer was washed with water and concentrated under reduce pressure at about 45°C to about 50°C.
  • reaction mixture was cooled, filtered and concentrated and demineralized water was added to it.
  • Ethyl acetate was added to the reaction mixture.
  • the reaction mixture was stirred and the two layers were separated. The organic layer was washed with water and concentrated to give a solid product.
  • a mixture of ivabradine hydrochloride (25g) and acetonitrile (500mL) was heated to about reflux temperature and was maintained at about the same temperature for about 30min.
  • the mixture was gradually cooled to about room temperature and was stirred for about 4h at about the same temperature.
  • the solid obtained was filtered, washed with acetonitrile and dried under vacuum.
  • the reaction mixture was stirred, concentrated at about below 50°C under reduced pressure and acetone (250mL) and demineralized water (250mL) was added to it.
  • the reaction mixture was heated to about 55°C to about 60°C and stirred for about lh at about the same temperature.
  • the reaction mixture was cooled to about room temperature.
  • the solid obtained was filtered, washed with water and dried at about 55°C to about 60°C for about 12h.
  • the reaction mixture was quenched into chilled demineralized water at about 5°C to about 10°C.
  • the reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the aqueous layer was basified to pH of about 8 to about 9.5 using 20-25% aqueous ammonia solution and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the organic layer was washed with demineralized water and concentrated under reduce pressure at about below 55°C.
  • reaction mixture 10% palladium charcoal was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm 3 to about 10kg/cm 3 at about 70°C to about 75°C for about 6h.
  • the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate.
  • the reaction mixture was concentrated at about below 50°C under reduced pressvire and acetonitrile and isopropyl alcohol hydrogen chloride (IPA-HC1) (30mL) was added to it at about 5°C to about 10°C. The reaction mixture was stirred for about 3h.
  • IPA-HC1 isopropyl alcohol hydrogen chloride
  • the reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile was added to it.
  • the reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about lh.
  • the reaction mixture was cooled and the solid obtained was filtered, washed with acetonitrile and dried at about 50°C to about 55°C for about 12h.
  • OVI Organic Volatile Impurity
  • reaction mixture 10% palladium charcoal was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm 3 to about lOkg/cm 3 at about 55°C to about 60°C for about lOh.
  • the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate.
  • the reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile and isopropyl alcohol hydrogen chloride (IPA-HCl) was added to it at about 5°C to about 10°C.
  • the reaction mixture was stirred at about 10°C to about 15°C for about 3h.
  • the reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile (500mL) was added to it.
  • the reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about lh.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and maintained at about the same temperature for about 2h.
  • the solid obtained was filtered and washed with acetonitrile.
  • the reaction mixture was quenched into chilled demineralized water at about 5°C to about 10°C.
  • the reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the aqueous layer was basified to pH of about 8 to about 9.5 using 20-25% aqueous ammonia solution and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the organic layer was treated with activated charcoal, stirred at about room temperature for about 30min, filtered over hyflo bed and washed with ethyl acetate.
  • the reaction mixture was stirred at about 10°C to about 15°C for about 3h.
  • the reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile (400mL) was added to it.
  • the reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about lh.
  • the reaction mixture was cooled and the solid obtained was filtered, washed with acetonitrile and dried at about 50°C to about 55°C.
  • reaction mixture 10% palladium charcoal (17g) was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm 3 to about 10kg/cm 3 at about 55°C to about 60°C for about 12h.
  • the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate.
  • the reaction mixture was concentrated at about below 50°C under reduced pressure. Demineralized water was added to the residue obtained.
  • the reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated.
  • the aqueous layer was basified to pH of about 8.5 using aqueous ammonia solution and ethyl acetate was added to it.
  • the reaction mixture was stirred and the two layers were separated.
  • the organic layer was washed with demineralized water and concentrated under reduce pressure at about 50°C to about 55°C to give an oily residue.
  • To the oily residue (90g) was added acetonitrile (900mL) and boric acid (59.37g) and the reaction mixture was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 80°C to about 85°C for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered and washed with acetonitrile.
  • acetonitrile (lOOOmL).
  • the reaction mixture was heated to about 80°C to about 85°C and methanol (65mL) was added to it at about the same temperature.
  • the reaction mixture was maintained at about 80°C to about 85°C for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25 °C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • reaction mixture was lyophilized by cooling to about - 84°C to about -65 °C under vacuum (not less than 1 OOmillitorr) for about 48h using lyophilizer instrument (Freeze dryer Vitris 4251 17).
  • a mixture of ivabradine (90g) and boric acid (59.37g) in acetone (900mL) was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 50°C to about 55°C for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered and washed with acetone.
  • acetonitrile 900mL
  • the reaction mixture was heated to about 80°C to about 85°C and methanol (65mL) was added to it at about the same temperature.
  • the reaction mixture was maintained at about 80°C to about 85°C for about 30min.
  • a mixture of ivabradine (2g) and boric acid (1.4g) in acetone (lOmL) and ethyl acetate (l OmL) was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 65°C to about 70°C for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered, washed with acetone and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • a mixture of ivabradine (3g) and boric acid (2g) in tetrahydrofuran (30mL) was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 60°C to about 65°C for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered, washed with tetrahydrofuran and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • a mixture of ivabradine (2.3g) and boric acid (1.52g) in acetonitrile (23mL) was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 80°C to about 85°C and ethanol (4.6mL) was added to it.
  • the reaction mixture was stirred, for about 30min at about the same temperature.
  • the reaction mixture was gradually cooled to about 20°C to about 25 °C and was maintained at about the same temperature for about 5h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • a mixture of ivabradine (lg) and boric acid (1.52g) in acetonitrile (lOmL) was stirred at about 20°C to about 25°C for about 30min.
  • the reaction mixture was heated to reflux at about 70°C to about 80°C and dimethyl sulfoxide (1.5mL) was added to it.
  • the reaction mixture was stirred for about 30min at about the same temperature.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 5h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • a mixture of ivabradine borate salt (50g) in acetonitrile (500mL) was heated to about 80°C to about 85°C and methanol (50mL) was added to it.
  • the reaction mixture was maintained at about the same temperature for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 24h.
  • a mixture of ivabradine borate salt (l g) in dimethyl formamide (2mL) was heated to about 60°C to about 65°C and acetonitrile (16mL) was added to it.
  • the reaction mixture was maintained at about the same temperature for about 3 ' 0min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 4h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 24h.
  • a mixture of ivabradine borate salt (2g) in acetonitrile (50mL) was heated to about 80°C to about 85°C and demineralized water (lmL) was added to it.
  • the reaction mixture was maintained at about the same temperature for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 4h.
  • the solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • a mixture of ivabradine borate salt (3g) in acetonitrile (30mL) was heated to about 50°C to about 55°C and demineralized water (I mL) was added to it.
  • the reaction mixture was maintained at about the same temperature for about 30min.
  • the reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 4h.
  • the solid obtained was filtered, washed with acetone and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 12h.
  • ivabradine hydrochloride To the 5d-crystalline form of ivabradine hydrochloride (5g), was added demineralized water (50mL) and the mixture was stirred for about 30min. The reaction mixture was treated with NoritTM charcoal and was stirred for about 30min. The reaction mixture was filtered over hyflo bed followed by micron filtration and washed with demineralized water. The reaction mixture was lyophilized by cooling to about -84°C to about -65°C under vacuum (not less than lOOmillitorr) for about 48h using lyophilizer instruments. Yield: 90%; HPLC purity: >99.5%

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Abstract

L'invention concerne un procédé de préparation de sels pharmaceutiquement acceptables d'ivabradine. L'invention concerne une forme amorphe de chlorhydrate d'ivabradine et un procédé de sa préparation.
PCT/IN2013/000809 2012-12-28 2013-12-27 Procédé de préparation d'ivabradine WO2014102827A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788377A (zh) * 2015-03-06 2015-07-22 浙江美诺华药物化学有限公司 一种伊伐布雷定及其药用盐的制备方法
CN104829530A (zh) * 2015-04-23 2015-08-12 扬子江药业集团北京海燕药业有限公司 一种无定型盐酸伊伐布雷定及其制备方法
WO2016026172A1 (fr) * 2014-08-22 2016-02-25 苏州亚宝药物研发有限公司 Chlorhydrate d'ivabradine amorphe et procédé de préparation et utilisations de celui-ci
CN107698509A (zh) * 2017-10-24 2018-02-16 重庆东得医药科技有限公司 一种脱氢伊伐布雷定草酸盐的制备方法
CN108424390A (zh) * 2018-01-25 2018-08-21 扬子江药业集团北京海燕药业有限公司 一种高纯度盐酸伊伐布雷定的制备方法
WO2019202611A1 (fr) * 2018-04-21 2019-10-24 Metrochem Api Pvt Procédé amélioré pour la synthèse de l'ivabradine ou de ses sels pharmaceutiquement acceptables
CN111220727A (zh) * 2020-01-17 2020-06-02 北京鑫开元医药科技有限公司海南分公司 盐酸伊伐布雷定中间体中对映异构体的检测方法及应用
CN114324715A (zh) * 2021-01-05 2022-04-12 海南鑫开源医药科技有限公司 7,8-二甲氧基-1,3-二氢-2h-3-苯并氮杂卓-2-酮中有关物质的检测方法

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WO2008146308A2 (fr) * 2007-05-30 2008-12-04 Ind-Swift Laboratories Limited Procédé de préparation de chlorhydrate d'ivabradine et polymorphe correspondant
CN101463008A (zh) * 2009-01-11 2009-06-24 山东鲁抗辰欣药业有限公司 盐酸伊伐布雷定无定型物及其制备方法
CN101597261A (zh) * 2008-06-06 2009-12-09 北京深蓝海生物医药科技有限公司 无定形盐酸伊伐布雷定
WO2010072409A1 (fr) * 2008-12-22 2010-07-01 Krka, D. D., Novo Mesto Procédé pour la préparation d'ivabradine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008146308A2 (fr) * 2007-05-30 2008-12-04 Ind-Swift Laboratories Limited Procédé de préparation de chlorhydrate d'ivabradine et polymorphe correspondant
CN101597261A (zh) * 2008-06-06 2009-12-09 北京深蓝海生物医药科技有限公司 无定形盐酸伊伐布雷定
WO2010072409A1 (fr) * 2008-12-22 2010-07-01 Krka, D. D., Novo Mesto Procédé pour la préparation d'ivabradine
CN101463008A (zh) * 2009-01-11 2009-06-24 山东鲁抗辰欣药业有限公司 盐酸伊伐布雷定无定型物及其制备方法

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016026172A1 (fr) * 2014-08-22 2016-02-25 苏州亚宝药物研发有限公司 Chlorhydrate d'ivabradine amorphe et procédé de préparation et utilisations de celui-ci
CN104788377A (zh) * 2015-03-06 2015-07-22 浙江美诺华药物化学有限公司 一种伊伐布雷定及其药用盐的制备方法
CN104788377B (zh) * 2015-03-06 2017-04-19 浙江美诺华药物化学有限公司 一种伊伐布雷定及其药用盐的制备方法
CN104829530A (zh) * 2015-04-23 2015-08-12 扬子江药业集团北京海燕药业有限公司 一种无定型盐酸伊伐布雷定及其制备方法
CN107698509A (zh) * 2017-10-24 2018-02-16 重庆东得医药科技有限公司 一种脱氢伊伐布雷定草酸盐的制备方法
CN107698509B (zh) * 2017-10-24 2020-04-21 重庆东得医药科技有限公司 一种脱氢伊伐布雷定草酸盐的制备方法
CN108424390A (zh) * 2018-01-25 2018-08-21 扬子江药业集团北京海燕药业有限公司 一种高纯度盐酸伊伐布雷定的制备方法
WO2019202611A1 (fr) * 2018-04-21 2019-10-24 Metrochem Api Pvt Procédé amélioré pour la synthèse de l'ivabradine ou de ses sels pharmaceutiquement acceptables
CN111220727A (zh) * 2020-01-17 2020-06-02 北京鑫开元医药科技有限公司海南分公司 盐酸伊伐布雷定中间体中对映异构体的检测方法及应用
CN111220727B (zh) * 2020-01-17 2022-04-26 北京鑫开元医药科技有限公司海南分公司 盐酸伊伐布雷定中间体中对映异构体的检测方法及应用
CN114324715A (zh) * 2021-01-05 2022-04-12 海南鑫开源医药科技有限公司 7,8-二甲氧基-1,3-二氢-2h-3-苯并氮杂卓-2-酮中有关物质的检测方法
CN114324715B (zh) * 2021-01-05 2023-06-02 海南鑫开源医药科技有限公司 7,8-二甲氧基-1,3-二氢-2h-3-苯并氮杂卓-2-酮中有关物质的检测方法

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