Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to substantially pure Vilazodone Hydrochloride, process for preparation of the same and also relates to an isolated impurity of Vilazodone.
• Vilazodone hydrochloride can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by product of the reaction, products of side reactions, impurities coming from the starting material or degradation products. It is essential to verify the identity of the source material and to establish its quality otherwise impurities associated with the raw materials may be carried through the manufacturing process to contaminate the final product.
• the process for preparation of Vilazodone illustrated in example-4 of US'241 involves reacting 5-(4-(4-(5- cyano-lH-indol-3-yl)butyl)piperazinyl-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l- methylpyridinium methanesulfonate in the presence of N-methyl pyrrolidine followed by treatment with dried ammonia gas to afford compound of formula I after customary workup.
• the Vilazodone thus obtained was further converted to its hydrochloride salt.
• the experimental procedure of the salification step is not elaborated in the specification.
• Figure - 1 is an illustration of NMR spectrum of compound of formula (5)
• Figure - 2 is an illustration of IR spectrum of compound of formula (5)
• Figure - 3 is an illustration of Mass spectrum of compound of formula (5)
• Figure - 4 is a representative HPLC chromatogram from an analysis of isolated compound of formula (5) labeled as VLZRC-6
• Figure - 5 is a representative HPLC chromatogram from an analysis of pure Vilazodone containing compound of formula (4) and formula (5) labeled as VLZRC-5 and VLZRC-6, respectively. Description of the invention
• the present invention is directed to provide an improved process for preparation and purification of Vilazodone, which when subsequently converted to its hydrochloride provides a substantially pure Vilazodone Hydrochloride free of undesired by-products or impurities.
• the present invention provides an environment friendly cost effective process for obtaining Vilazodone in higher purity and higher yield.
• the crude Vilazodone used in the present invention for purification purpose can be obtained as per a process demonstrated in prior art or by the process of the present invention.
• One aspect of the present invention provides an improved process for the preparation of the crude Vilazodone comprising of condensing 5-(piperaziny-l-yl)-l-benzofuran-2- carboxamide (PBA) of formula (2) with 3-(4-chlrobutyl)-lH-indole-5-carbonitrile (CBCI) of formula (3) in the presence of a condensing agent and solvent. Thereafter the crude Vilazodone is isolated from the reaction mixture by techniques known in the art such as filtration, centrifugation or the like and subjected to purification. The purification process affords the substantially pure Vilazodone of formula (1) which is optionally converted to its pharmaceutically acceptable salts.
• PBA piperaziny-l-yl)-l-benzofuran-2- carboxamide
• CBCI 3-(4-chlrobutyl)-lH-indole-5-carbonitrile
• Another aspect of the present invention provides condensation of compound of formula (2) and formula (3) to obtain compound of formula (1) in the presence of condensing agent and solvent.
• the suitable solvent medium for the reaction is an alcoholic solvent
• alcoholic solvent refers to alcoholic solvent selected from CI to C4 straight or branched chain alcohol containing more than 50% of water, more preferably more than 70% of water or most preferably more than 80% of water.
• the CI to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol.
• the preferred alcohol of the present invention is isopropanol.
• the condensing agent is a base selected from a group consisting of inorganic base.
• the suitable inorganic base includes sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium bicarbonate, calcium carbonate and cesium bicarbonate.
• condensation of compound of formula (2) with compound of formula (3) is carried out at a temperature of about 5 °C to about 110 °C, more preferably at about 25 °C to 90 °C or more preferably at reflux temperature of the reaction mixture.
• the reaction of compound of formula (2) with compound of formula (3) may be carried for about 5 hrs to about 24 hrs, more preferably for about 5 hrs to 12 hrs.
• the crude Vilazodone can be isolated using known techniques in the art such as decantation, filtration by gravity or suction or centrifugation.
• the crude vilazodone obtained by reaction of compound of formula (2) and (3) is slurry washed with water miscible solvent.
• the suitable water miscible solvent may be alcohol such as methanol and ketones such as acetone.
• slurry washing and/or wash and/or washes refers to a agitating a compound with solvent and thereafter isolating the compound by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
• the process involves purification of crude Vilazodone by charcoalisation of a solution of crude Vilazodone base in an amide solvent such as dimethylformamide(DMF) and N-Methyl pyrrolidine(NMP), followed by treating the filtrate with aqueous sodium metabisulfite, whereupon the pure Vilazodone precipitates which is collected by filtration.
• an amide solvent such as dimethylformamide(DMF) and N-Methyl pyrrolidine(NMP)
• the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in an amide solvent such as dimethylformamide (DMF) and N-Methyl pyrrolidine with aqueous sodium metabisulfite and an aqueous inorganic base.
• an amide solvent such as dimethylformamide (DMF) and N-Methyl pyrrolidine
• the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in dimethylformamide with aqueous sodium metabisulfite and aqueous inorganic base solution added in combination or separately in sequence.
• aqueous sodium metabisulfite and aqueous inorganic base solution in combination or separately in sequence, is gradually added to solution of crude Vilazodone in dimethylformamide .
• the inorganic base is selected from sodium carbonate, potassium carbonate and cesium carbonate.
• the aqueous inorganic base used in combination with sodium metabisulphite or separately is preferably sodium carbonate.
• the said addition is done in about 15 min. to 90 min., more preferably in 45 min. to 60 min.
• the addition is carried out at a temperature of 5 °C to 60 °C, more preferably at 20 °C to 40 °C and the resulting reaction mixture is stirred for 60-90 min, at 20-35 °C, whereupon the precipitated Vilazodone is collected and washed with water and acetone at ambient temperature to afford pure Vilazodone.
• the compound of formula ( 1 ) obtained by the present invention can be optionally converted into its pharmaceutically acceptable salts, for example hydrochloride salt by any of the method known in the art.
• the Vilazodone hydrochloride salt can be isolated by techniques known in the art such as filtration by gravity or suction, decantation or centrifugation
• the above mentioned production method is employed to prepare compound of formula (1) substantially free of dimer impurity, 5-(4-(4- (5-cyano-l-(4-(5-cyano-lH-indol-3-yl) butyl)- lH-indol-3-yl) butyl) piperazin-l-yl) benzofuran-2-carboxamide, compound of formula (4)
• the process involves purification of crude Vilazodone base involving acid-base treatment of solution of crude Vilazodone base in an amide solvent, which is preferably dimethylformamide ( DMF) before treatment with aqueous sodium metabisulphite to obtain pure Vilazodone, in effect, free of impurity of formula (5) as illustrated in example-4.
• an amide solvent which is preferably dimethylformamide ( DMF) before treatment with aqueous sodium metabisulphite to obtain pure Vilazodone, in effect, free of impurity of formula (5) as illustrated in example-4.
• the invention is directed towards isolated Vilazodone impurity, 5-(4-((3- (4-(4-(2-carbamoylbenzofuran-5-yl) piperazin-l-yl) butyl)-5-cyano-lH-indol-l-yl) methyl) piperazin-l-yl) benzofuran-2-carboxamide of formula (5).
• the isolated compound (5) of the present invention is used as reference marker and/or standard while testing the purity of Vilazodone and its pharmaceutically acceptable salt.
• a reference marker/standard is used for qualitative analysis and is also used to quantify the amount of the compound of the reference standard in an unknown mixture.
• the term "isolated” refers to a compound that is at least 80%, preferably at least 90%, even more preferably at least 93% pure measured as area percentage by HPLC.
• the formation of impurity of formula (5) in Vilazodone can be controlled within regulatory limits by purifying the commercially obtained raw material 5-(piperaziny-l-yl)-l-benzofuran-2-carboxamide (PBA) compound of formula (2) by acid-base treatment in water, as per example-5.
• the compound of formula (2) used for preparation of Vilazodone and its pharmaceutically acceptable salt has formaldehyde content not more than 500ppm (parts per million), more preferably not more than 300 ppm , most preferably not more than lOOppm.
• the impurity of formula (5) in crude Vilazodone is removed by treating a solution of crude Vilazodone with IPA-HCl, collecting the precipitated solid, treating the collected solid with dimethylformamide and liquor ammonia to obtain a solution which is further treated with aqueous sodium metabisulphite and sodium carbonate as illustrated in example-4.
• Pure Vilazodone obtained by the process of the present invention is further converted to its pharmaceutically acceptable salts by the processes known in the art.
• substantially pure Vilazodone hydrochloride is obtained by treating pure Vilazodone with IPA-HCl at 60-70°C, cooling the reaction mass to room temperature and then collecting the desired substantially pure Vilazodone Hydrochloride by filtration.
• IPA-HCl refers to solution of hydrochloride gas in isopropanol.
• Purity obtained of the purified Vilazodone using the process of the present invention is >99% by HPLC and that of substantially pure Vilazodone hydrochloride is >99% by HPLC.
• Vilazodone base and Vilazodone hydrochloride prepared according to the processes of the present invention can be substantially pure having purity greater than about 99% or greater than about 99.5% , or greater than about 99.7% or greater than about 99.9% as determined using high performance liquid chromatography (HPLC).
• Vilazodone base and Vilazodone hydrochloride produced by a method of present invention can be substantially pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.
• Vilazodone base and Vilazodone hydrochloride produced by the methods of present invention can be substantially pure having purity in amounts greater than about 99.8% and containing no single impurity in amounts greater than about 0.1% by HPLC.
• crude Vilazodone and/or crude Vilazodone base refers to solid obtained after condensation of compound (2) and (3) which is subjected to a purification process.
• Vilazodone and/or Vilazodone base and/or pure Vilazodone and/or pure Vilazodone base refers to substantially pure compound of formula (1).
• Vilazodone hydrochloride refers to hydrochloride salt of compound of formula (1).
• a compound is substantially pure if it comprises less than 0.2 %, preferably less than 0.15%, more preferably less than 0.1 % or most preferably less than 0.05% of impurity of formula (4) & (5) measured as area percentage by HPLC.
• the compound (5) of the invention has utility as a reference marker for Vilazodone and Vilazodone hydrochloride because it is a potential contaminant arising from side reactions which occur during the synthesis of the drug substance.
• the test sample of drug substance to be analyzed is assayed by one or more conventional analytical techniques.
• the analytical technique includes high performance liquid chromatography (HPLC) which is used for detection and quantification of impurities in a principal compound such as the drug substance. Detection and especially quantification of components of a mixture can be accomplished with the use of response factors.
• HPLC high performance liquid chromatography
• the response of a detector in HPLC e.g. UV detectors or refractive index detectors
• Response factors as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
• Analytical Methods Vilazodone Hydrochloride impurities may be determined using HPLC with the following chromatographic conditions
• Mobile phase-B Homogenous mixture of Buffer-B (aqueous ammonium acetate; 4.62 gm in 350ml HPLC grade water) and acetonitrile (35:65). Adjust pH of the mixture to 8.9 ⁇ 0.05 with ammonia. Mix well and sonicate to degas.
• Buffer-B aqueous ammonium acetate; 4.62 gm in 350ml HPLC grade water
• acetonitrile 35:65. Adjust pH of the mixture to 8.9 ⁇ 0.05 with ammonia. Mix well and sonicate to degas.
• Typical retention times that may be obtained are as follows:
• the reaction mass was heated to reflux (75-85 °C) and maintained for about 12 hrs (CBCI content is NMT 5.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) and the wet solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (500ml) and filtered through celite to remove insoluble. To the filtrated was added IPA.HC1 and the reaction mass was stirred for 60-90 min. The precipitated solid was collected by filtration, washed with DMF suck dried well.
• the wet cake was taken in a RBF and to it was added dimethylformamide. Thereafter liquor ammonia was added till pH 8.0-10.0 is obtained, the reaction mass was stirred for 30-45 min. and filtered through celite. To the filtrate was gradually added an aq. solution of sodium metabisulphite (15gm) and sodium carbonate (15 gm) in 400ml water in 45-60 min. The reaction mass was stirred for 60-90 min. the precipitated solid was collected by filtration and slurried with water, suck dried followed by slurry wash with acetone. The wet solid obtained after filtration was dried under vacuum to yield pure Vilazodone base.
• DMF 600ml
• lOOgm Vilazodone Hydrochloride
• reaction mass was then heated to reflux (75-85deg) and maintained for about 12 hrs (till CBCI content NMT 2.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water (500ml) and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) for 30-45min. The solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (700ml) and filtered through celite to remove insoluble. The celite bed was washed with DMF (lOOml).The DMF filtrate and washings were combined and preserved.
• MASS Spectra is recorded by dissolving sample in methanol using Xevo G2 QT of mass spectrometer m/z amu (atomic mass unit) Assignment

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• 2014
  • 2014-06-11 IN IN2001MU2013 patent/IN2013MU02001A/en unknown
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