WO2014049612A2 - Procédés et polymorphes de 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-pipérazinyl]-2-benzofuran carboxamide et ses sels - Google Patents

Procédés et polymorphes de 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-pipérazinyl]-2-benzofuran carboxamide et ses sels Download PDF

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WO2014049612A2
WO2014049612A2 PCT/IN2013/000580 IN2013000580W WO2014049612A2 WO 2014049612 A2 WO2014049612 A2 WO 2014049612A2 IN 2013000580 W IN2013000580 W IN 2013000580W WO 2014049612 A2 WO2014049612 A2 WO 2014049612A2
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formula
compound
cyano
indol
butyl
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PCT/IN2013/000580
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WO2014049612A3 (fr
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Sunkara VISHNUVARDHAN
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Msn Laboratories Limited
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    • 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

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  • the present invention provides an improved process for the preparation of antidepressant drug i.e., 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la represented by the following structural formula:
  • the present invention relates to novel crystalline forms of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1 and its pharmaceutically acceptable salts.
  • the present invention also relates to novel acid addition salts of 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and process for the preparation thereof.
  • the major drawback of the "241" process is that, it involves reaction of 5-(4-(4-(5-cyano- lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid in the presence of 2-chloro-l- methylpyridinium methanesulfonate to provide compound of formula- 1 with low yield and purity.
  • the said 2-chloro-l -methylpyridinium methanesulfonate is an expensive reagent, not suitable for commercial scale-up process.
  • the said process requires tedious work-ups to provide compound of formula- 1.
  • the 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide compound of formula-1 is reported as a crystalline solid in example-2 of US 7799916B2. Further, the said patent does not provided any physical characteristic data.
  • the crystalline 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained by the process of prior art is hereinafter designated as crystalline form-S.
  • the PXRD of said crystalline form-S is characterized by its X-ray diffractogram having peaks at 5.2, 7.6, 10.5, 14.3, 14.9, 15.3, 16.0, 17.7, 18.5, 19.7, 20.5, 21.0, 22.0, 22.9, 24.2, 24.8, 26.1, 28.8, 29.6, 30.9, 33.0, 33.3 and 34.5 ⁇ 0.2 degrees of two-theta having PXRD pattern as illustrated in figure- 1.
  • US7834020 describes several crystalline forms of vilazodone hydrochloride, such as Form-I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI and process for their preparation.
  • C 102219783 A discloses crystalline form of vilazodone dihydrochloride and process for its preparation.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile or improved shelf-life.
  • the present invention involves the novel crystalline forms of vilazodone free base as well as novel acid addition salts of vilazodone.
  • the present invention also provides novel acid addition salts of vilazodone in solid state form.
  • novel salts of vilazodone of the present invention can be used to prepare vilazodone free base in pure form, which in turn useful in the preparation of highly pure vilazodone hydrochloride.
  • the first aspect of the present invention is to provide a process for the preparation of 5- [4-[4-(5-cyano- 1 H-indol-3 -yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.
  • the second aspect of the present invention is to provide crystalline form-S of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • the third aspect of the present invention is to provide a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1, comprising of, amidating the ethyl 5-(4-(4-(5-cyano-lH- indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate compound of formula- 11 with a suitable amidation agent in the presence of a suitable base in a suitable solvent to provide crystalline from-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1.
  • the fourth aspect of the present invention is to provide crystalline 1,4-dioxane solvate form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride hereinafter designated as form-M.
  • the fifth aspect of the present invention is to provide process for the preparation of crystalline 1,4-dioxane solvate form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]- 2-benzofuran carboxamide hydrochloride.
  • the sixth aspect of the present invention is to provide a process for the preparation of 3- (4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of reacting 3-(4- chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6 with a suitable base in a suitable solvent to provide compound of formula-7.
  • the seventh aspect of the present invention is to provide novel crystalline form of 5-[4- [4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- 1 b hereinafter designated as form-N.
  • the eighth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb.
  • the ninth aspect of the present invention is to provide crystalline form-M of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1.
  • the tenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • the eleventh aspect of the present invention is to provide a novel crystalline form of 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1 hereinafter designated as form-N.
  • the twelfth aspect of the present invention is to provide a novel crystalline form of 5-[4- [4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la hereinafter designated as form-S.
  • the thirteenth aspect of the present invention is to provide a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.
  • the fourteenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • the fifteenth aspect of the present invention is to provide acid addition salt of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12.
  • the sixteenth aspect of the present invention is to provide a process for the preparation of acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12.
  • the seventeenth aspect of the present invention is to provide novel crystalline form of 5- [4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate hereinafter designated as form-R.
  • the eighteenth aspect of the present invention is to provide a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • Figure 1 Illustrates the PXRD pattern of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • Figure 2 Illustrates the DSC thermogram of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • Figure 3 Illustrates the PXRD pattern of crystalline 1,4-dioxane solvate form of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride.
  • Figure 4 Illustrates the PXRD pattern of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methane sulfonate compound of formula- lb.
  • Figure 5 Illustrates the PXRD pattern of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • Figure 6 Illustrates the PXRD pattern of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.
  • Figure 7 Illustrates the PXRD pattern of crystalline form-S of 5-[4-[4-(5-cyano- lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.
  • Figure 8 Illustrates the PXRD pattern of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • Figure 9 Illustrates the DSC thermogram of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl) butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • Figure 10 Illustrates the IR spectrum of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl) butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • the "suitable solvent” is selected from “alcoholic solvent” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butylether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, carbon tet
  • the “base” is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert- butoxide, potassium ethoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tribiityl amine, 4-dimethylaminopyridine, N-methyl morpholine, imidazole and the like.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide
  • the "reducing agent" is selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, triethylsilane, sodium borohydride/BF 3 -etherate, vitride, sodiumborohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN and trifluoroacetic acid/sodiumborohydride.
  • the "amidation agent” is selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines.
  • phase transfer catalyst is selected from tetra alkyl/aryl ammonium halides such as tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenyl phosphonium bromide.
  • TBAB tetra butyl ammonium bromide
  • tributyl benzyl ammonium bromide tetraoctyl ammonium bromide
  • the suitable “acid” is selected from “organic acids” such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfoic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid and the like.
  • the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
  • the first aspect of the present invention provides a process for the preparation of 5-[4-[4- (5-cyano- 1 H-indol-3-yl) butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, comprising of the following steps:
  • the crystalline solid compound of formula- 1, on treatment with aqueous hydrochloric acid provides crystalline form- VIII of compound of formula- 1 a.
  • the prior reported processes including the present invention disclosed the usage of tnfluoroacetic acid and NaBH 4 for the reduction of keto group of 3-(4-chlorobutanoyl)-l-tosyl- lH-indole-5-carbonitrile compound of formula-5, that requires high amounts of tnfluoroacetic acid which is not advisable to conduct the experiments in laboratory and also not recommended for the commercial level process.
  • the process of the present invention involves the usage of T1CI4 and triethyl silane in lower amounts for the above said reduction step.
  • T1CI4 is cheaper & safe when compare to tnfluoroacetic acid, hence it is more advantageous and recommended for the commercial level process.
  • the preferred embodiment of the present invention is to provide an improved process for the preparation of 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6, comprising of reducing the compound of formula-5 with triethylsilane in presence of titanium tetrachloride in methylene chloride provides 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6.
  • the second aspect of the present invention provides crystalline form-S of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, characterized by:
  • the third aspect of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, comprising of: a) adding a suitable solvent to ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride compound of formula- 1 la,
  • the suitable base is selected from inorganic base or organic base and suitable solvent is selected from polar aprotic solvents, alcoholic solvents, ester solvents, ether solvents, keto solvents, chloro solvents and hydrocarbon solvents or mixture thereof;
  • the step-(b), (c), (d) and (e) are carried out at a temperature ranges from -10 to 20°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 , comprising of:
  • US 5,532,241 discloses a process for the preparation of compound of formula-1 by the reaction of 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l-methylpyridinium methane sulfonate and N-methyl pyrrolidine in the presence of ammonia gas.
  • the said process involves the usage of expensive and complex reagent which leads to * tedious and complicated workup process to provide compound of formula-1 with low yield.
  • Journal of medicinal chemistry-2004, 47, 4684-4692 discloses the reaction of 5-(4-(4-(5- cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l- methylpyridinium iodide in the presence of ethyl diisopropyl amine to provide compound of formula- 1.
  • the said process involves the usage of fairly expensive or unfriendly reagent like 2- chloro-l-methylpyridinium iodide, which leads to low yield of compound of formula- 1 with complicated purification process.
  • the present invention is carried out in the presence of formamide and sodium methoxide, which are cheaper reagents and are environmental user friendly reagents when compared to the prior art. Moreover the present invention also reduces the cycle time of the reaction and avoids tedious work up process to provide compound of formula- 1 as crystalline solid with high yield and purity.
  • the compound of formula- 1 obtained according to the present invention having HPLC purity of greater than 99.5%, which is further useful in the preparation of highly pure compound of formula- la.
  • the fourth aspect of the present invention provides crystalline 1,4-dioxane solvate form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride hereinafter designated as form-M characterized by its powder X-ray diffractogram having peaks at 2.7, 10.6, 13.5, 13.8, 14.6, 16.2, 17.2, 18.0, 19.1, 19.7, 20.3, 21.1, 21.8, 22.2, 22.8, 26.5, 27.3, 28.0 and 31.3 ⁇ 0.2 degrees of two-theta as illustrated in figure-3.
  • the fifth aspect of the present invention provides a process for the preparation of crystalline 1,4-dioxane solvate form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-
  • 1,4-dioxane solvate crystalline form-M is useful for the preparation of pure 5-[4-[4- (5-cyano- 1 H-indol-3-yl) butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.
  • the sixth aspect of the present invention provides a process for the preparation of 3-(4- chlorobutyl)- 1 H-indole-5-carbonitrile compound of formula-7, comprising of:
  • the suitable base is selected from inorganic bases and organic bases as defined above and the suitable solvent is selected from ether solvents, alcoholic solvents, chloro solvents and mixture thereof and the suitable temperature is 25°C - 40°C.
  • the preferred embodiment of the present invention provides a process for the preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of,
  • the seventh aspect of the present invention provides novel crystalline form of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb hereinafter designated as form-N, characterized by its powder X-ray diffractogram having peaks at 5.6, 6.3, 7.0, 7.4, 9.5, 10.3, 1 1.7, 12.6, 13.7, 14.2, 14.7, 15.0, 15.2, 16.3, 16.7, 17.1, 17.9, 18.4, 18.7, 19.1, 19.5, 19.8, 20.4, 20.8, 21.8, 22.4, 22.8, 23.7, 24.3, 24.6, 25.0, 25.8, 26.2, 26.5, 27.7, 28.5, 29.0, 30.9, 31.5, 32.3, 34.3, 35.3 and 42.5 ⁇ 0.2 degrees of two- theta as illustrated in figure-4.
  • the eighth aspect of the present invention provides a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb, comprising of:
  • the suitable solvent used is selected from ether solvents, polar aprotic solvents, hydrocarbon solvents, ester solvents, chloro solvents or mixtures thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methane sulfonate compound of formula- lb, comprising of:
  • the crystalline form-S of compound of formula- 1 of the present invention can be useful in the preparation of salts of compound of formula- 1 i.e., crystalline form-M and crystalline form-N.
  • the crystalline form-M of 1,4-dioxane solvate compound of formula- la is also useful in the preparation of highly pure compound of formula- la.
  • the crystalline form-N of compound of formula- lb is useful in the preparation of highly pure compound of formula- la.
  • the ninth aspect of the present invention provides novel crystalline form-M of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 characterized by its X-ray powder diffraction pattern having peaks at 5.8, 7.4, 1 1.0, 13.4, 13.8, 16.1, 17.2, 18.5, 19.1, 20.0, 20.8, 21.4, 21.9, 24.3, 25.3, 26.8, 27.2, 28.0 and 27.5 ⁇ 0.2 degrees of two-theta as illustrated in figure-5.
  • the tenth aspect of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, which comprises of;
  • step d) distilling off the solvent from filtrate, e) slurrying the compound obtained in step d) in a suitable solvent,
  • the suitable solvent is . selected from nitrile solvents, ketone solvents, alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents like water or mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 , which comprises of;
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, which comprises of;
  • step d) slurrying the compound obtained in step d) in water
  • the eleventh aspect of the present invention provides a novel crystalline form-N of 5-[4-
  • the thirteenth aspect of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, which comprises of;
  • the suitable solvent is selected from chloro solvents, ketone solvents, ester solvents, alcohol solvents, hydrocarbon solvents, ether solvents, polar aprotic and polar solvents like water and/or their mixtures thereof.
  • the preferred embodiment of the present invention provides a process for the preparation0 of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butylJ-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, which comprises of; a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la in formic acid,
  • the fourteenth aspect of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, comprises of,
  • the suitable solvent is selected from ketone solvents, hydrocarbon solvents, ester solvents, ether solvents and chloro solvents, alcohol solvents, polar aprotic solvents, polar solvents and/or their mixture thereof.
  • the fifteenth aspect of the present invention provides acid addition salts of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12 with a proviso that, the acid is other than hydrochloride acid or methane sulfonic acid.
  • the term "Acid” represents inorganic acids such as hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, pyruvic acid, hexanoic acid, ethane sulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzene sulfonic acid, para toluene sulfonic acid, 4-methylbenzene sulfonic acid, naphthalene- 1,5-disulfonic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 4-amino benzoic acid, 4- hydroxybenzoic acid, 2-acetoxybenzoic acid, 2,4,6-trimethyl benzoic acid, succinic acid, mandelic acid, acetyl mandelic acid;
  • the preferred embodiment of the present invention provides acid addition salts of 5- [4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12 in crystalline solid form, wherein the suitable acid is preferably selected from hydrobromic acid, phosphoric acid, nitric acid, benzene sulfonic acid and para toluene sulfonic acid.
  • acid-addition salt compounds of general formula- 12 can be converted into pure 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 by treating the compound of formula- 12 with a suitable base in a suitable solvent.
  • the suitable base is selected form alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof.
  • the sixteenth aspect of the present invention provides a process for the preparation of acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12, comprises of reacting the compound of formula- 1 with a suitable acid in a suitable solvent provides corresponding acid addition salt compound of general formula- 12.
  • the suitable acid is same as defined in fifteenth aspect of the present invention; and the suitable solvent is selected from ketone solvents, hydrocarbon solvents, ester solvents, ether solvents and chloro solvents, alcohol solvents, polar solvents, polar aprotic solvents, nitrile solvents or mixtures thereof.
  • the seventeenth aspect of the present invention provides novel crystalline form of 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate hereinafter designated as form-R, characterized by:
  • the eighteenth aspect of the present invention provides a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of;
  • the suitable hydrochloride source is selected from HC1 gas, aqueous HC1, dry HCl, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
  • the suitable temperature is ranging from 0°C to 100°C, preferably 25°C to
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of;
  • US7834020 discloses crystalline vilazodone dihydrochloride form-XIII characterized by its powder X-ray diffractogram having peaks at about 13.4, 14.4, 16.3, 17.5, 18.1, 20.4, 20.63, 21.2, 26,0, and 28.3 ⁇ 0.2 degrees of two theta.
  • the present invention provides crystalline form-R of vilazodone dihydrochloride monohydrate characterized by its powder X-ray diffractogram having peaks at about 5.6, 7.6, 10.8, 11.2 15.0, 15.3, 15.6, 16.0, 21.5, 22.3, 22.6, 23.2, 24.7, 25.1, 25.8, 26.8, 27.2, 29.2, 29.9, 30.6 and 34.0 ⁇ 0.2 degrees of two theta.
  • the compound of formula- la produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • DSC Differential scanning calorimetric
  • a liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry CI 8, 150 x 4.6mm, 3.5 ⁇ (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Column Temperature: 40°C; Injection volume: 5 ⁇ ; Run time: 35 min; Diluent: Water : Isopropyl alcohol (1 : 1) v/v; Needle wash: Water : Isopropyl alcohol (1 : 1) v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30) v/v; Buffer: 2.72 grams of potassium dihydrogen phosphate and 3.0 grams of 1 -Octane sulphonic acid in 1000 ml of water. Adjust pH to 2.0 with diluted orthophosphoric acid and filtered through 0.22 ⁇ Nylon membrane filter paper and sonicate to degas it.
  • Example-1 Preparation of l-Tosyl-lH-indoIe-5-carbonitrile (Formula-3)
  • Example-3 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile (Formula-6) Trifluoroacetic acid (100 ml) was added to a mixture of dichloromethane (50 ml) and 3- (4-chlorobutanoyl)-l-tosyl-lH-indole-5-carbonitrile (10 g) at 25-30°C. The reaction mixture was cooled to 0 - 10°C and sodium borohydride (5.54 g) was added to the reaction mixture at 0-5°C. Stirred the reaction mixture at 10 - 15°C for 5 hours. After completion of the reaction, quenched the reaction mixture with hydrochloric acid solution. Stirred the reaction mixture for 1 hour at 30-35°C. Filtered the precipitated solid and washed with water and dried to get the title compound. Yield: 9.1 gm; Melting point: 96-100°C.
  • Potassium carbonate (0.36 g) was added to a mixture of 3-(4-chlorobutyl)-l-tosyl-lH- indole-5-carbonitrile (1 g), methanol (5 ml) and tetrahydrofuran (10 ml) and heated to 50-55°C. The reaction mixture was stirred for 3 hours at 50-55°C. The reaction mixture was cooled to 25- 35°C and water was added to it. The reaction mixture was stirred further about 45 minutes at 25- 35°C. Filtered the precipitated solid and then dried to get title compound. Yield: 0.5 g
  • Example-7 Preparation of ethyl 5-(piperazin-l-yI)benzofuran-2-carboxylate hydrochloride (Formula-10)
  • Example-8 Preparation of ethyl 5-(4-(4-(5-cyano-lH-indoI-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride (Formula-lla)
  • Example-13 Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide methanesulfonate (Formula-lb)
  • Example-15 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (Formula-1)
  • Acetonitrile (300 ml) was added to the wet compound obtained in example- 14 and heated to 80-85°C and stirred for 1 hour. Filtered the reaction mixture and washed with acetonitrile at the same temperature. Distilled off the solvent completely from the filtrate to obtain the crude compound. Acetonitrile (30 ml) was added to the crude compound and stirred for 2 hours at 25- 30°C. Filtered the solid and washed with acetonitrile. Water (300 ml) was added to the wet compound and was heated to 90-95°C. Stirred the reaction mixture for 30 minutes at 90-95°C. Cooled the reaction mixture to 30-35°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the crystalline form-M.
  • the PXRD of the crystalline form-M is shown in figure-5.
  • Example-24 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l- piperazinyl]-2-benzofuran carboxamide from isopropanol (Formula-1) 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (2.0 g) was dissolved in isopropanol (100 ml) at 80-85°C. Slowly cooled the reaction mixture to 25-30°C and then further cooled to 5-10°C. Stirred the reaction mixture for 2 hours at 5-10°C. Filtered the precipitated solid, washed with chilled isopropanol and dried to get the title compound. Yield: 1.7 g.
  • Example-25 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyI]-2-benzofuran carboxamide from tetrahydrofuran (Formula-l)
  • Example-26 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yI)butyI]-l- piperazinyl]-2-benzofuran carboxamide from ethyl acetate (Formula-l)
  • Example-29 Preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (Formula-1)
  • Example-31 Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (Formula-1). 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide Para toluene sulfonate (5 gm) and acetone (30 ml) were charged into a clean and dry RBF at 25-30°C. Basifying the reaction mixture with aqueous sodium carbonate solution. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.
  • Example-33 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide from tetrahydrofuran (Formula-1).
  • Example-34 Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyI]-2-benzofuran carboxamide from water (Formula-1).
  • Acetonitrile (300 ml) was added to the obtained wet compound and heated to 80-85°C and stirred for 1 hour. Filtered the reaction mixture and washed with acetonitrile at the same temperature. Distilled off the solvent completely from the filtrate to obtain the crude compound. Acetonitrile (30 ml) was added to the crude compound and stirred for 2 hours at 25-30°C. Filtered the solid and washed with acetonitrile. Water (300 ml) was added to the wet compound and was heated to 90-95°C. Stirred the reaction mixture for 30 minutes at 90-95°C. Cooled the reaction mixture to 30-35°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound; Yield: 21 gms.
  • Example-36 Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate
  • Example-37 Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • Example-38 Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.
  • Aluminium chloride (235 gms) was slowly added to dichloromethane (1000 ml) under nitrogen atmosphere at 25-30°C.
  • 4-chlorobutanoyl chloride (149 gms) was added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature.
  • the organic layer obtained in example-39 was added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature.
  • reaction mixture was slowly added to water and stirred for 15 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined both the organic layers.
  • Aqueous sodium bi carbonate solution was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature.
  • Dichloromethane 700 ml was added to 3-(4-chlorobutanoyl)-l-tosyl-lH-indole-5- carbonitrile (100 gms ) at 25-30°C. Cooled the reaction mixture to 0-5°C. Titanium tetrachloride ⁇ titanium tetrachloride (59.18 gms) dissolved in dichloromethane (300 ml) ⁇ solution was slowly added to the reaction mixture at 0-5°C. Triethyl silane (145 gms) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hours at the same temperature.
  • reaction mixture was added to chilled water (1000 ml) at 0-5°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer is extracted with dichloromethane. Combined both the organic layers and washed with water and then followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Methanol (300 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with methanol to get the title compound.
  • Acetone (1500 ml) and dimethyl sulfoxide (400 ml) were added to 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (100 gms) at 25-30°C.
  • Heated the reaction mixture to 55-60°C and hydrogen peroxide (61.6 gms) was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 14 hours at 50-60°C. After completion of the reaction, cooled the reaction mixture to 25-30°C.
  • Water (3000 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
  • the obtained compound was purified by column chromatography.
  • Methnaol 160ml was added to ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride (20 gms) at 25-30°C.
  • Sodium hydroxide 11.65 gms was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and water was added to it and further cooled to 10-15°C.
  • the pH of the reaction mixture was adjusted to 5.5 by using dilute hydrochloric acid at 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 12 gms.
  • Example-46 Purification of ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yI)benzofuran-2-carboxy!ate hydrochloride (Formula-lla)
  • Ethyl alcohol (60.0 ml) was added to a mixture of methanol (60.0 ml), water (60.0 ml) and 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (2.0 gms) at 25-30°C and stirred for 10 minutes at the same temperature.
  • Hydrochloric acid (0.54 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and distilled off the solvent completely from the reaction mixture to get the title compound. Yield: 1.6 gms.
  • Example-51 Preparation of . Amorphous 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride
  • Diethylene glycol monoethyl ether 500 ml was added to ethyl 5-aminobenzofuran-2- carboxylate (100 gms) at 25-30°C.
  • Bis-(2-chloroethyl)amine hydrochloride 87.2 gms
  • potassium iodide 8.1 gms
  • tetrabutyl ammonium bromide 7.85 gms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé perfectionné pour la préparation de médicament antidépresseur, c'est-à-dire d'un composé chlorhydrate de 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-pipérazinyl]-2-benzofuran carboxamide répondant à la formule la représentée par la formule développée suivante : (Ia) T
PCT/IN2013/000580 2012-09-27 2013-09-26 Procédés et polymorphes de 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-pipérazinyl]-2-benzofuran carboxamide et ses sels WO2014049612A2 (fr)

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CN105541811A (zh) * 2016-01-08 2016-05-04 万特制药(海南)有限公司 一种抗抑郁药物维拉佐酮的精制方法
WO2016128987A1 (fr) * 2015-02-13 2016-08-18 Harman Finochem Limited Procédé de préparation de la base libre 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1h-indol-3-yl)butyl]-1-pipérazinyle], et de son sel chlorhydrate
US9533949B2 (en) 2012-09-12 2017-01-03 Apotex Pharmachem Inc. Processes for the preparation of 3-alkyl indoles
CN106518853A (zh) * 2016-09-22 2017-03-22 北京万全德众医药生物技术有限公司 一种盐酸维拉佐酮杂质的制备方法
WO2023173182A1 (fr) * 2022-03-16 2023-09-21 Eurofarma Laboratórios S.A. Sel de docusate de vilazodone, procédé d'obtention, composition pharmaceutique et utilisation

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UA76758C2 (uk) * 2001-06-19 2006-09-15 Мерк Патент Гмбх Поліморфні форми гідрохлориду 1-'4-(5-ціаноіндол-3-іл)бутил-4-(2-карбамоїлбензофуран-5-іл)піперазину
CN102219783B (zh) * 2011-05-05 2013-07-03 天津市汉康医药生物技术有限公司 盐酸维拉佐酮及其组合物
US9505744B2 (en) * 2011-11-23 2016-11-29 Assia Chemical Industries Ltd. Solid state forms of vilazodone and vilazodone hydrochloride
CN102617558A (zh) * 2012-03-26 2012-08-01 上海泛凯生物医药科技有限公司 一种维拉佐酮的制备方法
WO2013156935A1 (fr) * 2012-04-16 2013-10-24 Ranbaxy Laboratories Limited Procédé de préparation de cristaux de chlorhydrate de vilazodone
CN102977083A (zh) * 2012-12-17 2013-03-20 南京海纳医药科技有限公司 1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨甲酰-苯并呋喃-5-基)-哌嗪盐酸盐的新晶型xⅶ及其制备方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9533949B2 (en) 2012-09-12 2017-01-03 Apotex Pharmachem Inc. Processes for the preparation of 3-alkyl indoles
WO2016128987A1 (fr) * 2015-02-13 2016-08-18 Harman Finochem Limited Procédé de préparation de la base libre 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1h-indol-3-yl)butyl]-1-pipérazinyle], et de son sel chlorhydrate
CN105541811A (zh) * 2016-01-08 2016-05-04 万特制药(海南)有限公司 一种抗抑郁药物维拉佐酮的精制方法
CN106518853A (zh) * 2016-09-22 2017-03-22 北京万全德众医药生物技术有限公司 一种盐酸维拉佐酮杂质的制备方法
WO2023173182A1 (fr) * 2022-03-16 2023-09-21 Eurofarma Laboratórios S.A. Sel de docusate de vilazodone, procédé d'obtention, composition pharmaceutique et utilisation

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