WO2014083571A1 - Procédé de préparation d'alcaftadine - Google Patents

Procédé de préparation d'alcaftadine Download PDF

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Publication number
WO2014083571A1
WO2014083571A1 PCT/IN2013/000420 IN2013000420W WO2014083571A1 WO 2014083571 A1 WO2014083571 A1 WO 2014083571A1 IN 2013000420 W IN2013000420 W IN 2013000420W WO 2014083571 A1 WO2014083571 A1 WO 2014083571A1
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Prior art keywords
formula
compound
alcaftadine
acceptable salts
pharmaceutically acceptable
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PCT/IN2013/000420
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English (en)
Inventor
Ravi Ponnaiah
Arshad Moosa HASHMI
Praveen Kumar Neela
Dhanunjaya Naidu SEEMALA
Raviteja MOKKA
Anandkumar Madanlal LAHOTI
V. P. S. S Deepthi
G. Srinivas Pardha SARADHI
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Neuland Laboratories Limited
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Publication of WO2014083571A1 publication Critical patent/WO2014083571A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to a process for the preparation of A lcaftadine.
  • the invention also relates to a process for the preparation of crystal line form of Alcaftadine. .
  • a lcaftadine is chem ical ly known as 6, 1 1 -dihydro- l ] -( l -methyl-4-piperidinyl idene)-5H- im idazo[2, 1 -b] [3] benzazepine-3-carboxaldehyde having the formula as represented below:
  • Alcaftadine is used for the treatment of histam ine H I receptor antagonist.
  • the US Patent US5468743 first discloses the Alcaftadine and also the process for the preparation of Alcaftadine.
  • the process in US'743 ' patent involves the steps of: reaction of piperidin-4-yl,6, 1 1 -dihydro-5H- im idazo[2, l -b][3]benzazepine with formaldehyde and form ic acid to obtain a compound methylpiperidin-4-yl,6, 1 l -dihydro-5H-im idazo[2, l -b][3]benzazepi ne; and reaction of the obtained compound with formaldehyde and acetic acid in presence of sodi um acetate to yield the compound methylpiperidin-4-y 1,6, 1 1 -dihydro-5 H-im idazo[2, l -b] [3]benza
  • the disclosed process employs the column chromatography for isolation of intermediate as well as for Alcaftad ine.
  • Practicing of column chromatography at commercial scale is cumbersoine.Therefore, there is a need to develop a process for preparing Alcaftadine, which is cost effective, commercially viable and does not employ any column chromatographic techinques.
  • the primary object of the invention is to provide an improved process for preparation of Alcaftadine or its pharmaceutical ly acceptable salts.
  • Another object of the invention is to provide a process for preparation of novel crystal l ine form of
  • a further object of the invention is to provide a process for purification of Alcaftadine or its pharmaceutical ly acceptable salts.
  • the invention provides a process for preparation of Alcaftadine or its pharmaceutical ly acceptable salts comprising the steps of : i) cyclizing a compound of formula ⁇
  • trifl ic acid triflurosu lfon ic acid
  • Formula VII iii) reacting the compound of formula VII with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.
  • theinvention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) cyclizing a compound of formula IV
  • triflurosulfonic acid triflic acid
  • the invention provides a process for preparation of Alcaftadine or its pharmaceutical acceptable salts comprising the steps of : . i) treating the compound of formula VI
  • the invention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) cyclizing the compound of formula 111 A
  • the invention provides a process for preparation of Alcaftadine or its pharmaceutical acceptable salts comprising the steps of :
  • the invention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) reacting the compound of formula V
  • step (ii) washing the reaction mixture obtained in step (i) with acetonitrile;
  • step (iii) reacting the washed reaction mass obtained in step (ii) with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.
  • theinvention provides a process for purification of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of:
  • step (ii) optionally, heating the solution obtained in step (i);
  • step (iii) optionally, cooling the solution obtained in step (i) or step (ii);
  • step (iv) adding a second organic solvent to the solution obtained in step (i) or (ii) or (iii);
  • step (v) maintaining the contents obtained in step (iv) till the formation of solid
  • the first organic solvent is selected from the ester or mixtures containing the ester thereof: the second solvent is selected from the aliphatic hydrocarbons or mixtures containing the aliphatic hydrocarbons thereof.
  • the invention provides a crystalline form of the compound 11-
  • the invention provides a process for preparing a Crystalline form of Alcaftadine comprising the steps of:
  • step (ii) optionally, cooling the solution obtained in step (i);
  • step (iii) adding the aliphatic hydrocarbon solvent to the solution obtained in step (i) or (ii);
  • step (iv) maintaining the mixture resulted in step (iii) till the formation of crystalline form.
  • Figure- 1 represents typical X-ray powder diffraction pattern of the crystalline form of the compound 1 l-(piperidin-4-ylidene)-6, 1 l-dihydro-5H-imidazo[2, l-&][3]benzazepine
  • Figure 2 represents DSC of the crystalline form of the compound 1 l-(piperidin-4- ylidene)-6,l l-dihydro-5H-imidazo[2, 1 -/>][3]benzazepine
  • Figure 3 represents TGA of the crystalline form of the compound 11 -(piperidin-4- ylidene)-6, 11 -dihydro-5H-imidazo[2, 1 -6][3]benzazepine
  • Figure 4 Figiire-4 represents typical X-ray powder diffraction pattern of crystalline Alcaftadine
  • Figure 5 represents DSC of crystalline Alcaftadine form
  • Figure 6 represents TGA of crystalline Alcaftadine form DETAILED DESCRIPTION OF THE INVENTION
  • the invention provides improved process for preparation of Alcaftadine or its pharmaceutically acceptable salts which are cost effective and commercially viable.
  • the invention provides a novel process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) treating a compound of formula I
  • R is a leaving group
  • the base empolyed in the step i) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise CI- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or flouro aniline, flouro methyl phenyl amine and ammonia .
  • the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise CI- C6 carbons containing amines such as alkyl amines
  • the base empolyed in the step ii) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise CI- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or fluoro aniline, flouro methyl phenyl amine and ammonia .
  • the invention provided a process for preparation of Alcaftadine or its pharmaceutically acceptable salts, comprising the steps of : i) treating a compound of formula 1
  • the base empolyed in the step i) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise Cl- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or flouro aniline, flouro methyl phenyl amine and ammonia .
  • the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise Cl- C6 carbons containing amines such as alkyl amines like
  • the base empolyed in the step i i) is selected form the group comprising of organ ic or inorganic bases, wherein, the inorgan ic bases comprise alkal i metal hydroxides l ike sod ium hydroxide, potassium hydroxide, alkal i metal carbonates like sodium carbonates, potassium carbonates, alkal i metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise C I - C6 carbons containing am ines such as alkyl amines like methyl am ine, ethyl am ine, aryl am ines or substituted aryl amines like ani line, benzyl am ine, or flouro anil ine, flouro methyl phenyl amine and ammonia .
  • the inorgan ic bases comprise alkal i metal hydroxides l ike sod ium hydroxide, potassium hydroxide, alkal i metal carbonates like sodium carbonates, potassium carbonates, alkal i metal bicarbonates like sodium bi
  • the methylating reagent empolyed in the step v) is selected form the group comprising of methyl hal ides, dimethyl carbonate, dimethyl su lfate, phosgene or a m ixture of formaldehyde and form ic acid.
  • the patent US5468743 describes an alkylating reaction of the com pound with formaldehyde and acetic acid in the presence of sodium acetate to obtain an alkylated compound; This method involves column chromatography for the purification of the alkylated compound and is not efficient. Unexpectedly the inventors of the present invention found that the use of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the starting material increases the yield of the product and decreases the formation of impurities.
  • the invention provides a process for preparation of A lcaftad ine or its pharmaceuticaly acceptable salts comprising the steps of : i) treating the compound of formu la V I
  • Formula VII i i) treating the compound of formu la VI I with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.
  • triflurosulfon ic acid triflic acid
  • the reaction of the compound having formu la VI I contain ing an impurity compound of formu la VI I I, with manganese dioxide resu lts in the formation of A lcaftad ine along with formation of impurities.
  • the present inventors found that the purification of A lcaftad ine resulted in such processes involves cumbersome purification techniques.
  • the inventors of the present invention developed a novel technique for the preparation, wherein the impurity having the formu la VI II in the compound having form ula VII is removed after the reaction with manganese d ioxide by washings with acetonitri le thereby separating the purified unreacted compound of formula V I I and l ittle amount of Alcaftadine. The separated A lcaftadine was then reacted with manganese dioxide to obtaine pure Alcaftadine.
  • a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) reacting the compound of formula VII
  • step (ii) washing the reaction mixture obtained in step (i) with acetonitrile;
  • step (iii) reacting the the washed reaction mass obtained in step (ii) with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.
  • the step (i) and (iii) may be carried out in any conventionally used suitable organic solvent.
  • suitable organic solvents include dichloromethane, chloroform, acetonitrile, toluene, and n-hexane.
  • step (ii) optionally, heating the solution obtained in step (i);
  • step (iii) optionally, cooling the solution obtained in step (i) or step (ii);
  • step (iv) adding a second organic solvent to the solution obtained in step (i) or (ii) or (iii); (v) maintaining the contents obtained in step (iv) till formation of the solid;
  • the first organic solvent is selected from the ester or mixtures containing the ester thereof; the second solvent is selected from the aliphatic hydrocarbons or mixtures containing the aliphatic hydrocarbons thereof.
  • the ester organic solvent used herein is selected from the group comprising of Butyl acetate Sec- Butyl acetate, Tert-butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl acetate, Isopropyl acetate, Methyl acetate and the likes.
  • the aliphatic hydrocarbon organic solvent used herein is selected from the group comprising of pentane, hexane, heptanes, octane, petroleum ether and the likes.
  • the invention provides a crystalline form of the compound 1 l-(piperidin-4- ylidene)-6, 1 l-dihydro-5H-imidazo[2, l-£][3]benzazepine as represented below:
  • the process for preparing crystalline form of the compound 11 -(piperid in-4-y I idene)-6, 11- dihydro-5H-imidazo[2,l -6][3]benzazepine comprises the steps of:
  • the invention provides a process for preparing a Crystalline form of Alcaftadine comprising the steps of:
  • step (ii) optionally, cooling the solution obtained in step (i);
  • step (iii) adding a aliphatic hydrocarbon solvent to the solution obtained in step (i) or (ii);
  • step (iv) maintaining the mixture resulted in step (iii) till the formation of crystalline form.
  • the ketone solvent used in step (i) is selected from the group comprising of acetone, methyl ketone and the likes.
  • the aliphatic hydrocarbon organic solvent used in step (iii) is selected from the group comprising of pentane, hexane, heptanes, octane, petroleum ether and the likes.
  • Imidazole (67.0 gm), potassium carbonate (136.0 gm) and tetrabutyl ammonium bromide (16.0 gm) was added at 25-30°C, heated to 104-110 °C and stirred for 1 hr at the same temperature. After the completion of the reaction, water (500 ml) was added and stirred for 30 minutes. The organic layer separated and washed with water. Water (500ml) was added to the organic layer and the pH of the contents was adjusted to 2 or below with hydrochloric acid. The aqueous layer was separated and toluene was added to the aqueous layer.
  • the biphasic medium was stirred for 15 minutes and adjusted to a pH of 10 to 14 with 10% aqueous sodium hydroxide solution. The temperature of the contents were raised to 25-30°C and stirred for 30 minutes at the same temperature. The organic layer was separated and disti lled off under vacuum at below 65°
  • the residue was cooled to 25-30°C and (249.57gm) aqueous HBr was added to the residue. The contents were stirred for 10 min; then heated to 85- 90°C and maintained for 12 hrs at the same temperature.
  • the reaction mass was cooled to 55-60°C and ( 167.5 ml). Isopropyl alcohol was added to the cooled reaction mass, then heated to 65-70°C and maintain for 1 hr at the same temperature.
  • the reaction mass was filtered and dried the material in hot air oven at 60-65°C for 8 hrs.
  • the dried solid was suspended in tetrahydrofuran (3.0 volumes to above dry compound) and heated to reflux temperature to obtain a clear solution.
  • the contents were cooled to 25-30°C, followed further cooling to 0-5°C and stirred for 1.0 hr at the same temperature.
  • the contents were filtered and washed with chilled tetrahydrofuran (0.2 volumes) and dried the compound under vacuum at 50-55°C.
  • the compound obtained in example-5 (100 g) was mixed with acetic acid (50 ml), 37% aqueous formaldehyde (500 ml) and potassium acetate 12.29 g at 25-30 °C and heated the reaction mixture to 100°C. The reaction mixture was maintained for 10-13 hours at 100°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 25-30 °C and dichioromethane (1000 ml) was added. The pH of the reaction mass was adjusted to 11-12 with 20% aqueous sodium hydroxide and stirred for 10-15 min. The organic layer was separated, washed brine solution and dehydrated by the addition of sodium sulphate (200 g) and filtered.
  • Step-A To a solution of the compound obtained in example-6 (110.8 g) in Chloroform 1000 ml, manganese dioxide (311.5 g) was added at 25 °C and heated to 55-65°C. The reaction mixture was maintained for 2 hours at the 55-65°C. The progress of the reaction was monitored by HPLC. The reaction was stopped if the HPLC shows diol impurity below 0.75%, the reaction mixture was cooled to 25-30°C, filtered through hyflow and washed with dichioromethane (500 ml). The washings of dichioromethane and the chloroform filtrate was combined and concentrated below 60°C to obtain a residue.
  • Step-B To the solid obtained during filtration, chloroform (750 inL) and manganese dioxide (211 gm) was added at a temperature of 25-30°C. The reaction mixture was heated to 55-65°C and maintained at the same temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 25-30°C; filtered through hyflow and washed with dichioromethane (500 ml).
  • Step-C The wet solid obtained in step-B was mixed with acetonitrile (150 ml) and refluxed at 75-
  • Step-D The wet solid obtained in step-C was mixed with acetonitrile (150 ml) and refluxed at 75- 85°C. Acetonitrile was slowly added to the contents till formation of a clear solution. The contents were then cooled to I0-15°C and maintained for 1 hour at the same temperature. The obtained solid was filtered and washed with chilled acetonitirile (12.5 ml).
  • Step-E (Purification of the Alcaftadine) The wet solid obtained in step-D was refluxed with ethyl acetate (25 ml) at 75-80°C for 1 hour. The contents were then cooled to 0-5°C.
  • Step-A To a solution of the compound obtained in example-6 (110.8 g) in Chloroform 1000 ml, manganese dioxide (311.5 g) was added at 25 °C and heated to 55-65°C. The reaction mixture was maintained for 2 hours at the 55-65°C. The progress of the reaction was monitored by HPLC. The reaction was stopped if the HPLC shows diol impurity below 0.75%, the reaction mixture was cooled to 25-30°C, filtered through hyflow and washed with dichloromethane (500 ml). The washings of dichloromethane and the chloroform filtrate was combined and concentrated below 60°C to obtain a residue.
  • the residue was mixed with dichloromethane (750 ml) and refluxed at 35- 40°C for 15 minutes and cooled to 25 to 30°C.
  • the cooled solution filtered through hyflow and the bed hyflow was washed with dichloromethane (250 ml).
  • the filtrate and washings were combined to obtain a residue.
  • the residue was acetonitrile (300 ml) and stirred for 1 hour at 25-30°C.
  • the contents were filtered and washed with acetonitrile (50 ml).
  • the wet solid was mixed with acetonitrile (100 ml) and refluxed to 65-75°C for 1 hour.
  • the contents were the cooled to 25 to 30°C and maintained at the same temperature.
  • the resulted was filtered and washed with acetonitrile (25 ml).
  • Step-B To the solid obtained during filtration, chloroform (750 niL) and manganese dioxide (211 gm) was added at a temperature of 25-30°C. The reaction mixture was heated to 55-65°C and maintained at the same temperature for 2 hours. The progress of the reaction was monitored by
  • Step-C The wet solid obtained in step-B was mixed with acetonitrile (105 ml) and refluxed at 75- 85°C. Purified water (15 ml) was added to the contents till formation of a clear solution and refluxed at 75-80°C. The contents were filtered through hyflow at 75-80°C and wash the hyflow bed with hot acetonitrile (10 ml). The filtrate and washings were combined and refluxed at 75-80°C for 30 minutes. The refluxed contents were then cooled to 10-15°C and maintained for 1 hour at the same temperature. The resulted solid was filtered and washed with acetonitrile (10 ml).
  • Step-E (Preparation of crystalline Alcaftadine form)
  • the wet solid obtained in step-D was suspended in acetone (375 ml) and heated to a temperature of 50-55°C.
  • the contents were maintained and stirred at the temperature of 50-55°C till a clear solution was formed.
  • Activated charcoal (0.5 gm) was added to the solution and refluxed for 30 minutes at a temperature of 50- 55°C.
  • the contents were filtered through hyflow and washed the hyflow bed with hot acetone (50 ml).
  • the filtrate and the washings were combined at concentrated to obtain a residue.
  • the residue was mixed with acetone (25 ml) at 25-30°C and cooled to 0-5°C.
  • n-heptane 150 ml was added to the contents at 0-5°C and maintained at the same temperature for 1 hour at the same temperature.
  • the crystalline solid obtained was then filtered, washed with chilled n-heptane (10 ml) and dried in vacuum at 55-60°C for 6- 12 h. Yield: 18.5%.
  • Example - 9 Process for the preparation of l-(2-phenylethyl-lH-imidazole)
  • the 2-phenyl ethyl sulfonate (150 gm) was dissolved in THF at 25-30°C, followed by the imidazole (100.5 gm) was at same temperature.
  • the potassium carbonate (0.9 mol) was added at 25-30°C.
  • the temperature of the reaction mixture was raised to 70-75°C and stirred for 18-20 hours in the same temperature.
  • the reaction mixture was cooled to 25-30°C.
  • the contents were filtered and wash with the ethyl acetate (1000 ml).
  • the filtrate was distilled under vacuum and the residue was dissolved in (1500 ml) ethyl acetate at 25-30°C.
  • the hydrochloride solution was added to the reaction mixture. Aqueous layer was separated.
  • Example - 10 Process for the preparation of Ethyl 4- ⁇ [l-(2-phenylethyl)-lH-imidazole-2-yl] carbonyl ⁇ -l-piperidinecarboxylate
  • Example -12 Preparation of [l-(2-phenylethyl)-lH-imidazole-2-yl](4-piperidinyl)methanone
  • the compound of example-11 was dissolved in (900ml) 20% sodium carbonate solution and the pH of the reaction mixture was adjusted to 8-9, followed by the addition of (804 ml) methylene dichloride. The organic layer was separated and distilled to obtain the compound. Yield: 98%
  • Example-13 Preparation of ll-piperidin-4-ylidene-6, ll-dihydro-5H-imidazo[2,l- ][3)benzazepine
  • the compound of example- 12 (82 gm) was dissolved in (50 ml) methylene chloride at 25-30°C and heated to 40-45°C. Distilled the methylene chloride to get a concentrated mixure and cooled to 25- 30°C. The triflic acid (64 ml) was added to the reaction mixture and the reaction mixture was heated to I35-I40°C. The progress of the reaction was monitored by TLC. After the completion of the reaction mixture, the reaction mass cooled to 25-30°C and the pH of the reaction mixture was adjusted to 8-9 with 20% aq. Sodium carbonate solution (-800 ml). The methylene dichloride (410 ml) was added to the reaction mixture and stirred for 10 minutes.
  • the compound of example- 13 ( 34.4gm ) was added to (206 ml ) 37% formaldehyde solution at 25-30°C followed by 98% formic acid (69 ml ) was added to the reaction mixture at 25-30°C. The temperature of the reaction mixture was raised to 1 1 0°C. After the completion of the reaction, the reaction mixture was cooled to 25-30°C and the pH was adjusted to 8-9 with aq. Sodium carbonate solution. Methylene chloride (480 ml) was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated and disti lled to obtain the compound.
  • the compound of example- 14 was dissolved in (60 ml) 37% formaldehyde solution at 25-30°C and the temperature of the reaction was raised to l l 0°C. The reaction mixture was stirred at 1 10°C- 1 15°C till completion of reaction. The progress of the reaction was monitored by TLC. The reaction m ixture was cooled to 25-30°C and the pH of the reaction was adjusted to 8-9 with (50 ml) aq. Sodium carbonate solution. The reaction mixture was extracted with (70 ml) of methylene chloride. The organic layer was separated, washed with (50 ml) brine solution, dried over magnesium sulphate and concentrated the total organic layer on rota vapour at 40-45°C to get semi solid compound.
  • Example -16 Preparation of l l-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l- b] [3] benzazepine-3-carbaldehyde
  • Example - 18 Preparation of l-methylpiperidine-4-carbonyl chloride hydrochloride.
  • Example - 19 preparation of (l-methylpiperidine-4-yl)[l-(2-Phenylethyl)-lH-imidazol-2- yl]methanone Hydrobromide
  • reaction mixture was raised up to 25- 30°C and; water (53.5 ml), ethyl acetate (53.5 ml ) was added and stirred for 10 minutes. The organic layer was separated and washed with water. The organic layer was distilled and the resulting residue was dissolved in aqueous HBr (21.4 ml). The temperature of the contents was raised to 80-85°C. The progress of the reaction was monitored by TLC. After the completion of the reaction, distilled the reaction mixture at 70-75°C, then cooled the reaction mixture to 25-30°C and mixed with isopropyl alcohol (21.4 ml). The contents were filtered, the resulted compound was dried. Yield: 42%
  • Example- 20 Preparation of ll-(l-methyIpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l- A][3]benzazepine
  • Example - 21 purification of ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l- Z>][3]benzazepine-3-carbaldehyde
  • the resultant solid was filtered, dissolved in acetonitrile (147 ml) by refluxing to get a clear solution and the contents were maintained for 30 minutes. Then the contents were cooled to 0°C in 2 hours. The resultant solid was isolated, washed with precooled acetonitrile (21 ml) and dried at 40°C.

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Abstract

L'invention concerne un procédé amélioré pour la préparation d'alcaftadine, de sa forme cristalline ou de ses sels pharmaceutiquement acceptables ainsi qu'un procédé de purification d'alcaftadine ou de ses sels pharmaceutiquement acceptables.
PCT/IN2013/000420 2012-11-29 2013-07-08 Procédé de préparation d'alcaftadine WO2014083571A1 (fr)

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Cited By (5)

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CN104710427A (zh) * 2014-12-20 2015-06-17 威海法莫斯特医药技术开发有限公司 一种阿卡他定新晶型
CN104860888A (zh) * 2015-05-26 2015-08-26 南京华威医药科技开发有限公司 阿卡他定中间体及阿卡他定的合成方法
CN104987337A (zh) * 2015-07-28 2015-10-21 武汉武药科技有限公司 一种制备阿卡他定的新氧化方法
US9255105B2 (en) 2012-12-06 2016-02-09 Enaltec Labs Private Limited Process of preparing alcaftadine
KR20160018472A (ko) * 2013-03-25 2016-02-17 크리스탈 파마 에스.에이.유. 알카프타딘 및 이의 약제학적으로 허용가능한 염의 제조 방법

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US9255105B2 (en) 2012-12-06 2016-02-09 Enaltec Labs Private Limited Process of preparing alcaftadine
KR20160018472A (ko) * 2013-03-25 2016-02-17 크리스탈 파마 에스.에이.유. 알카프타딘 및 이의 약제학적으로 허용가능한 염의 제조 방법
KR102204578B1 (ko) 2013-03-25 2021-01-20 크리스탈 파마 에스.에이.유. 알카프타딘 및 이의 약제학적으로 허용가능한 염의 제조 방법
CN104710427A (zh) * 2014-12-20 2015-06-17 威海法莫斯特医药技术开发有限公司 一种阿卡他定新晶型
CN104860888A (zh) * 2015-05-26 2015-08-26 南京华威医药科技开发有限公司 阿卡他定中间体及阿卡他定的合成方法
CN104987337A (zh) * 2015-07-28 2015-10-21 武汉武药科技有限公司 一种制备阿卡他定的新氧化方法

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