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WO2009062036A2 - Procédés de préparation de lévocétirizine et de ses sels pharmaceutiquement acceptables - Google Patents

Procédés de préparation de lévocétirizine et de ses sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2009062036A2
WO2009062036A2 PCT/US2008/082802 US2008082802W WO2009062036A2 WO 2009062036 A2 WO2009062036 A2 WO 2009062036A2 US 2008082802 W US2008082802 W US 2008082802W WO 2009062036 A2 WO2009062036 A2 WO 2009062036A2
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Prior art keywords
formula
compound
solvent
chlorophenyl
phenylmethyl
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WO2009062036A3 (fr
Inventor
Srinivasan Thirumalai Rajan
Uppala Venkata Bhaskara Rao
Akundi Surya Prabhakar
Joga Rajender
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to processes for preparing levocetirizine and pharmaceutically acceptable salts thereof.
  • Levocetirizine dihydrochloride is the adopted name for a drug chemically described as (R)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy] acetic acid dihydrochloride, with molecular formula C2iH 2 5CIN 2 O3*2 HCI and is represented by the structural Formula I.
  • Levocetirizine dihydrochloride is a white, crystalline powder and is water soluble. It is used as an active and selective H1 -receptor antagonist and is marketed under the brand name as XYZAL® tablets in 5 mg strength.
  • Great Britain Patent No. 2225321 described a process for the preparation of cetihzine in the levorotatory or dextrorotatory form or a mixture of thereof comprising the hydrolysis of enantiomerically pure or racemic [2-[4-[(4- chlorophenyljphenylmethylj-i -piperazinyljethoxyj-acetonithle. Also, processes for preparing levocetirizine and dextrocetirizine from its racemic mixture or racemic intermediates were known in U.S. Patent No. 6977301 , and International Application Publication Nos. WO 2005/073207 and WO 2006/094648.
  • Literature records various processes wherein optically active intermediates have been employed for manufacturing levocetirizine, such as Great Britain Patent No. 2225321 , U.S. Patent Nos. 5478941 and 6803465, and International Application Publication Nos. WO 2007/066162 and WO 2007/066163.
  • U.S. Patent No. 5478941 disclosed the preparation/introduction of optical center in the early phase of the synthesis i.e. R-(-)-1 -(4-chlorophenyl)-phenylmethylamine followed by reaction with N,N-bis-(2-chloroethyl)4-methylbenzenesulfonamide to prepare optically active 1 -[(4-chlorophenyl)-phenylmethyl]-4-[p-toluenesulphonyl]- piperazine, which was subsequently crystallized.
  • Step (1 ) involves condensing (-)-4-chlorobenzhydrylamine of Formula VII
  • Suitable bases for Step (1 ) include organic bases, inorganic bases, and mixtures thereof.
  • Suitable inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • Suitable organic bases include methylamine, dimethylamine, triethylamine, N-ethyl diisopropylamine, butyl amine, and N-methyl morpholine.
  • the base is N,N-diisopropylethylamine.
  • the molar equivalent of base per compound of Formula Vl i.e., (-)-4- chlorobenzhydryl amine, may be about 2-4.
  • Suitable solvents for Step (1 ) include and are not limited to: alcohols, such as, for example, methanol, ethanol, and isopropyl alcohol; halogenated solvents, such as, for example, dichloromethane, dichloroethane, and chloroform; hydrocarbon solvents, such as, for example, toluene, xylene, cyclohexane, and heptane; ketones, such as, for example, acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; esters, such as, for example, ethyl acetate, n-propyl acetate, and isopropyl acetate; and mixtures thereof.
  • a solvent comprises methanol.
  • Suitable temperatures for conducting the reaction of Step (1 ) may range from about 30 0 C to about 14O 0 C or the reflux temperature of the solvent used.
  • the reaction may be carried out for a desired time period to achieve the desired product yield and purity, for example, from about 30 minutes to about 10 hours, or longer.
  • the completion of the reaction can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the reaction mass is cooled after completion of the reaction, methanol is added, cooled to ambient temperature to precipitate out the product, which is further cooled to less than about 10 0 C, aged for sufficient time to ensure complete precipitation of the compound.
  • the separated compound may be recovered from the reaction mixture by removal of solvent, by gravity filtration, filtration by suction or by centrifugation, followed by washing the compound with a suitable solvent, which may the same solvent used during precipitation of the product to wash out mother liquors occluded in the product.
  • the recovered product may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, rotatory dryer, and the like. Drying may be carried out at temperatures from about 25 0 C to about 75 0 C with or without vacuum and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. Drying may be carried out for a desired time period to achieve the desired product purity. Drying times from about 1 to about 15 hours, or longer, are frequently adequate.
  • the compound may optionally be recrystallized from a suitable solvent, which includes: alcohols such as methanol, ethanol, and isopropyl alcohol; halogenated solvents, such as dichloromethane, dichloroethane, and chloroform; hydrocarbon solvents, such as, toluene, xylene, cyclohexane, and heptane; ketones, such as, acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; esters, such as, for example, ethyl acetate, n-propyl acetate, and isopropyl acetate; and mixtures thereof.
  • a suitable solvent which includes: alcohols such as methanol, ethanol, and isopropyl alcohol; halogenated solvents, such as dichloromethane, dichloroethane, and chloroform; hydrocarbon solvents, such as, toluene, xy
  • Step (2) involves removing the 4-methoxyphenylsulfonyl group from the compound of Formula V using a deprotecting agent in the presence of organic solvent(s) to afford (-)-1 -[(4-chlorophenyl)phenylmethyl]-piperazine of Formula IV;
  • Suitable deprotecting agents for Step (2) include and are not limited to acids, such as, for example, hydrochloric acid and hydrobromic acid in their aqueous medium or purged in organic acids, such as, for example, acetic acid.
  • the deprotecting agent comprises hydrobromic acid.
  • suitable solvents include and are not limited to: alcohols, such as, for example, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, and tertiary- butyl alcohol; ketones, such as, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogenated solvents, such as, for example, dichloromethane, dichloroethane, and chloroform; hydrocarbon solvents, such as, for example, toluene, xylene, and cyclohexane; esters, such as, for example, ethyl acetate, isopropyl acetate, and tertiary butyl acetate; acetic acid and mixtures of acetic acid and acetic anhydride; water; and mixtures thereof in various proportions.
  • a solvent comprises glacial acetic acid.
  • Suitable temperature for conducting the reaction may range from about 15 0 C to about 90 0 C, or the reflux temperature of the solvent used.
  • the reaction may be carried out for a desired time period to achieve the desired product yield and purity. For example, the reaction time may be from about 30 minutes to about 10 hours.
  • the completion of the reaction can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the reaction mass is cooled to a lower temperature of about less than 40 0 C.
  • the reaction mass is diluted with water and washed with a suitable water immiscible solvent such as, an aliphatic or aromatic hydrocarbon for example, hexane, heptane, benzene, toluene, xylene etc.
  • a halogenated hydrocarbon such as, chloroform, dichloromethane, chlorobenzene or an ester such as, for example; ethyl acetate, isopropyl acetate, n-butyl acetate or an ether such as, for example diethyl ether, diisopropyl ether or a ketone such as methyl ethyl ketone, methyl isobutyl ketone or any suitable solvent as desired, to remove unreacted starting materials if any and to remove impurities.
  • a halogenated hydrocarbon such as, chloroform, dichloromethane, chlorobenzene or an ester
  • ethyl acetate isopropyl acetate
  • n-butyl acetate or an ether such as, for example diethyl ether, diisopropyl ether or a ketone such as methyl ethyl ketone, methyl isobutyl ketone
  • the product may be recovered by basification of the aqueous reaction mass to a pH of above 7.0, followed by extraction of the product into a suitable water immiscible solvent such as benzene, toluene, xylene, dichloromethane, chloroform ethyl acetate.
  • a suitable water immiscible solvent such as benzene, toluene, xylene, dichloromethane, chloroform ethyl acetate.
  • the organic layer obtained upon extraction followed by separation from the aqueous layer may be washed with water, followed by removal of the solvent by distillation.
  • the residue left after solvent removal is triturated with water and the separated solid is aged for suitable time and filtered to remove the solvent, washed with water to remove the occluded mother liquors and dried.
  • Step (3) involves condensing the compound of Formula IV with 2-chloroethanol of Formula III
  • Step (3) the molar equivalent of 2-chloroethanol per Formula IV may be about 1-5.
  • the bases suitable for Step (3) include and are not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium tehtarybutoxide, pyridine, N-methylmorpholine, diisopropylamine, triethylamine, diisopropylethylamine, and mixtures thereof.
  • the base comprises triethylamine.
  • the solvents suitable for Step (3) include and are not limited to: alcohols, such as, for example, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, and tertiary-butyl alcohol; ketones, such as, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone; hydrocarbon solvents, such as, for example, toluene, xylene, cyclohexane, and the like; esters, such as, for example, ethyl acetate, isopropyl acetate, tertiary butyl acetate, and the like; nitriles, such as, for example, acetonithle and propionitrile; aprotic polar solvents, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, dimethylacetamide, and N- methylpyrrolidinone; and mixture
  • Suitable temperatures for conducting the reaction of Step (3) may range from about 15 0 C to about 120 0 C, or the reflux temperature of the solvent used.
  • the reaction of Step (3) may be carried out for a desired time period to achieve the desired product yield and purity.
  • the reaction time may be from about 30 minutes to about 10 hours.
  • reaction mass may be cooled to a lower temperature and quenched with water, the compound is extracted with a suitable water immiscible solvent such as benzene, toluene, xylene, dichloromethane, chloroform, 1 ,2- dichloroethane, ethyl acetate, isopropyl acetate or n-butyl acetate.
  • Solvent is removed from the organic extract by distillation resulting in thick syrupy oil.
  • Step (4) reacting the compound of Formula Il with sodium monochloroacetate using suitable reagents in the presence of organic solvent(s) at suitable temperatures to afford (+)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1 -piperazinyl] ethoxy] acetic acid dihydrochloride of Formula I.
  • the molar equivalent of sodium monochloroacetate per the compound of Formula Il may be about 1-5.
  • Suitable bases for Step (4) include organic bases, inorganic bases, and mixtures thereof.
  • Suitable inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • Suitable organic bases include methylamine, dimethylamine, triethylamine, N-ethyldiisopropylamine, butylamine, and N-methylmorpholine.
  • a base comprises potassium carbonate.
  • the solvents suitable for Step (4) include and are not limited to: alcohols, such as, for example, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and tertiary-butyl alcohol; ketones, such as, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone; hydrocarbon solvents, such as, for example, toluene, xylene, cyclohexane, and the like; esters, such as, for example, ethyl acetate, isopropyl acetate, and tertiary butyl acetate; nitriles, such as, for example, acetonitrile, propionitrile, and the like; aprotic polar solvents, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, dimethylacetamide, and N- methylpyrrolidinone; and mixture
  • Suitable temperature for conducting the reaction of Step (4) may range from about 0 0 C to about 90 0 C, or the reflux temperature of the solvent used.
  • the reaction may be carried out for a desired time period to achieve the desired product yield and purity.
  • the reaction time for Step (4) may be from about 30 minutes to about 10 hours.
  • Suitable acids for acidification may be aqueous hydrochloride (5%-36%), hydrochloride in methanol, hydrochloride in isopropyl alcohol, hydrochloride in acetone, dry hydrochloride gas, and mixtures thereof.
  • reaction mass is quenched with water, and washed with a suitable water immiscible solvent such as, an aliphatic or aromatic hydrocarbon for example; hexane, heptane, benzene, toluene, xylene etc.
  • a suitable water immiscible solvent such as, an aliphatic or aromatic hydrocarbon for example; hexane, heptane, benzene, toluene, xylene etc.
  • a halogenated hydrocarbon such as, chloroform, dichloromethane, chlorobenzene or an ester such as, for example; ethyl acetate, isopropyl acetate, n-butyl acetate or an ether such as, for example diethyl ether, diisopropyl ether or a ketone such as methyl ethyl ketone, methyl isobutyl ketone or any suitable solvent as desired, to remove unreacted starting materials if any and to remove impurities.
  • a halogenated hydrocarbon such as, chloroform, dichloromethane, chlorobenzene or an ester
  • ethyl acetate isopropyl acetate
  • n-butyl acetate or an ether such as, for example diethyl ether, diisopropyl ether or a ketone such as methyl ethyl ketone, methyl isobutyl ketone
  • the aqueous reaction mass after removal of the undesired compounds is acidified with diluted aqueous hydrochloric acid to a pH of less than 4.5 and the product is extracted with a suitable water immiscible solvent such as benzene, toluene, xylene, dichloromethane, chloroform, 1 ,2-dichloroethane, ethyl acetate, isopropyl acetate or n-butyl acetate, followed by carbon treatment with activated charcoal and removal of the solvent.
  • Solvent may be removed by evaporation, distillation, distillation may be carried out atmospherically or under reduced pressure to yield the desired compound in the form of freebase as thick syrupy oil, which may optionally be converted to an acid additional salt using a pharmaceutically acceptable acid.
  • the syrupy oil obtained upon removal of the solvent may be converted to a hydrochloride salt by treating a solution of the compound in a suitable solvent such as acetone, methyl ethyl ketone, toluene, and ethyl acetate, preferably acetone, at a suitable temperature of from about 25 to 50 oC with hydrochloric acid.
  • a suitable solvent such as acetone, methyl ethyl ketone, toluene, and ethyl acetate, preferably acetone
  • the hydrochloride salt separated out is further maintained at about 25-35 oC for about 30 min. to 2.0 hrs, the product may be recovered from the reaction mass by filtration or centhfugation and may be washed with the same solvent to remove mother liquors trapped in the compound.
  • the recovered product may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, rotatory dryer, and the like. Drying may be carried out at temperatures from about 25 0 C to about 75 0 C with or without vacuum and in the presence or absence of an inert atmosphere like nitrogen. Drying may be carried out for a desired time period to achieve the desired product purity. Drying times from about 1 to about 15 hours, or longer, are frequently adequate.
  • the product may be purified if desired by conventional methods such as recrystallisation, purification by slurry or by regeneration of base followed by conversion to hydrochloride salt. Step (5) involves purifying the compound of Formula I by recrystallization or making a slurry in organic solvent(s).
  • Recrystallization involves providing a solution of crude levocetirizine or a salt thereof in a suitable solvent or mixture of solvents and then crystallizing the solid from the solution.
  • Suitable organic solvents in which levocetirizine or a salt may be dissolved for purification include and are not limited to: Ci-C 5 ketones, such as, for example, acetone, ethyl methyl ketone and butanone; alcohols, such as, for example, ethanol, methanol, and isopropanol; ethers, such as, for example, tetrahydrofuran and 1 ,4-dioxane, ethyl acetate; water; and mixtures thereof in various proportions without limitation.
  • the organic solvent comprises water and acetone.
  • Suitable temperatures for forming a solution for recrystallization may range from about 25 0 C to about 75 0 C, or from about 50 0 C to about 60 0 C, or about reflux temperature of the solvent used.
  • the concentration of the levocetirizine or its salt in the solvent(s) may range from about 15 % to about 95 %.
  • the solution may be prepared at an elevated temperature if desired to achieve a higher solute concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the levocetirizine or salt is obtained and the temperature is not detrimental to the drug substance chemically or physically. Further processing of the solution, if desired, is achieved by adjusting the temperature. A higher temperature for dissolution will allow the precipitation from solutions with higher concentrations of levocetirizine, resulting in better economies of manufacture. Crystal formation from the solution may be promoted by cooling the solution.
  • the recovered product may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, rotatory dryer, and the like. Drying may be carried out at temperatures from about 25 0 C to about 75 0 C with or without vacuum and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. Drying may be carried out for a desired time period to achieve the desired product purity. Drying times from about 1 to about 15 hours, or longer, are frequently adequate.
  • the present invention includes enantiomerically pure (-)-1 -[(4-chlorophenyl) phenylmethyl]-4-[(4-methoxyphenyl)sulfonyl] piperazine of Formula V, that is substantially pure of other process related impurities and optical impurities.
  • the present invention includes processes for preparing a compound of Formula IV by deprotecting a compound of Formula V, without using 4-hydroxy benzoic acid, wherein, the optical purity, as well as chemical purity, is retained in the compound of Formula IV without performing any additional step of recrystallization or puhfication(s).
  • the present invention includes processes for the preparation of substantially pure compound of Formula Il from compound of Formula IV, which does not require any purification, by techniques like chiral chromatographic separation or salt formation or recrystallization.
  • the present invention includes substantially pure levocetihzine or its salts.
  • substantially pure refers to chemical and optical purity of levocetirizine greater than 99 %, preferably 99.5 %, and more preferably 99.8 % by weight.
  • Levocetirizine and its pharmaceutically acceptable salts described herein and/or prepared in accordance with the processes described herein may contain less than about 0.5 %, or less than about 0.1 %, by weight of process, optical, or structural impurities as characterized by high performance liquid chromatography (HPLC) and chiral HPLC.
  • Levocetirizine dihydrochloride of Formula I may be analyzed by the HPLC, for example, by a method using a column LICROSPHER® silica, 250x4.0 mm ID, 5 ⁇ m or equivalent. The parameters are given in Table 1.
  • Levocetirizine dihydrochloride of Formula I may also be analyzed by a second HPLC method using a column INERTSIL® silica 250x4.6 mm ID, 5 ⁇ m particle size or equivalent. The parameters are given in Table 2.
  • optical purity of levocetihzine dihydrochloride of Formula I may be analyzed by chiral HPLC using a column CHIRALPAK® AD (4.6x250 mm). The parameters are given in Table 3.
  • the present invention includes pharmaceutical compositions comprising a therapeutically effective amount of substantially pure levocetirizine or a pharmaceutically acceptable salt thereof, containing less than about 0.20% of any individual impurity, together with one or more pharmaceutically acceptable excipients.
  • Suitable excipients for pharmaceutical compositions are well known in the art.
  • EXAMPLE 1 PREPARATION OF ( ⁇ 1 -[(4-CHLOROPHENYL)PHENYLMETHYL]- 4-[(4-METHOXYPHENYL)SULFONYL] PIPERAZINE
  • N,N-dichloroethyl-4-methoxybenzenesulfonamide (19.8 kg) are charged under stirring and the reaction mixture is heated to about 125 0 C to about 130 0 C.
  • the reaction mass is maintained under reflux at the same temperature for about 10 hours.
  • reaction mass is cooled from about 80 0 C to about 90 0 C.
  • Methanol 50 L is charged into the reactor and cooled to about 0 0 C to about 5 0 C, and the reaction mass is maintained at the same temperature for about 30 to about 60 minutes.
  • the separated solid is then centhfuged and the wet material in centrifuge is washed with methanol (12.5 L). The material is spin-dried for about 30 to about 60 minutes. The wet cake is further dried at about 60 0 C to about 70 0 C for about 3 to about 4 hours to afford 23.8 kg of the title compound. Yield: 90.83%, Purity by HPLC: 99.0%.
  • reaction mass is washed with toluene (2 ⁇ 45 L) at room temperature followed by cooling of the aqueous layer to 0-5 0 C and then the pH of the aqueous layer is adjusted to about 12.0 to about 14.0 at below 35 0 C using 40 % sodium hydroxide (67 L).
  • the reaction mass is then extracted with toluene (3*70 L) at about 40 0 C to about 45 0 C.
  • the combined organic layer is washed with water (2*25 L) and distilled off completely. To the residue so obtained, water (115 L) is charged at about 25 0 C to about 35 0 C and stirred at the same temperature for about 2-4 hours.
  • a mixture of 2-chloroethanol (7.95 kg), (-)-1 -[(4-chlorophenyl)phenylmethyl]- piperazine (23 kg) and triethylamine (9.58 kg) are charged in a clean and dry reactor and heated to about 80-85 0 C for about 45-60 minutes.
  • the reaction mass is further heated to about 90-95 0 C and stirred at the same temperature for about 45-60 minutes.
  • the reaction mass is further heated to about 96-105 0 C for about 4 hours.
  • the reaction mass is cooled to about 65-75 0 C and water (144 L) is charged and stirred for about 15 minutes.
  • reaction mass is then extracted with toluene (68 L), subsequently washed with toluene (2*23 L), and the combined organic layer is washed with water (3*68 L).
  • the solvent is distilled off completely under vacuum at below 100 0 C and cooled to 50-55 0 C to afford 24 kg oily residue of the title compound. Yield: 90.49%, Purity by HPLC: 97.83%.
  • EXAMPLE 4 PREPARATION OF (+)-2-[4-[(4-CHLOROPHENYL) PHENYL METHYL]-1 -PIPERAZINYL] ETHOXY ACETIC ACID DIHYDROCHLORIDE
  • Caustic potash flakes (6.8 kg) are slowly added to a mixture of N,N-dimethyl- formamide (40 L) and (-)-2-[4-[(4-chlorophenyl)phenylmethyl]-1 -piperazinyl] ethanol (13 kg) in a clean and dry reactor at about 0-5 0 C.
  • the reaction mass is stirred at about 5-10 0 C for about 1-1.5 hours.
  • Sodium monochloroacetate (7.1 kg) is added at about 5-10 0 C into the reactor and the reaction mixture is stirred at the same temperature for about 1-1.5 hours. The temperature is then raised to about 25 0 C to about 35 0 C and stirred for about 10 hours. After the completion of the reaction, water (145 L) is charged and stirred for about 15 minutes. The reaction mass is then washed with toluene (4 ⁇ 25L) at about 40-45 0 C. The pH of the aqueous layer is then adjusted to about 4.0 to about 4.5 with 36 % hydrochloric acid (11 L) at about 25-35 0 C. The aqueous layer is then extracted with dichloro methane (2 ⁇ 41 L).
  • the combined dichloromethane layer is washed with saturated sodium chloride solution (2 ⁇ 41 L) and water (2 ⁇ 40 L).
  • the organic layer is then treated with charcoal at reflux temperature, filtered through hyflow and washed hyflow with dichloromethane (83 L).
  • the organic layer is distilled off initially at atmospheric condition and then under vacuum at about 650 ⁇ 50 mmHg at below 60 0 C.
  • the residue is cooled to about 40-50 0 C and acetone (202 L) is charged.
  • Hydrochloric acid (36 %, 7.8 L) is slowly added at about 40-45 0 C in about 1-1.5 hr and it is stirred at the same temperature for about 1-1.5 hr.
  • reaction mass is then cooled to about 25-35 0 C and stirred for about 30-60 minutes at the same temperature.
  • the separated solid is then centrifuged and washed with acetone (15 L).
  • the material is spin-dried for about 30-60 minutes.
  • the wet cake is initially air dried and further dried at about 60-70 0 C for about 4 hours then cooled to 25-30 0 C, pulverized to afford 10.5 kg of the title compound. Yield: 55.70%, Purity by HPLC: 99.78%.
  • EXAMPLE 5 PURIFICATION OF (+)-2-[4-[(4-CHLOROPHENYL) PHENYL METHYL]-1 -PIPERAZINYL] ETHOXY ACETIC ACID DIHYDROCHLORIDE Water (2.3 L), acetone (64L) and (+)-2-[4-[(4-Chlorophenyl) phenyl methyl]-1 - piperazinyl] ethoxy acetic acid dihydrochlohde (10.5 kg) are charged in a clean dry reactor and the reaction mixture is heated to reflux for about 4-5 hours. The reaction mass is then cooled to about 25-35 0 C and maintained at the same temperature for about 30-60 minutes.
  • Example 2.3 of U.S. Patent No. 5478941 ) in 6 ml_ (4.4 g or 0.0343 mol) of ethyldiisopropylamine are mixed in a 25 ml_ round-bottomed flask.
  • the mixture is heated under reflux (127 0 C) for 4 hours and then cooled, with stirring, to 86 0 C and 13.8 ml_ of methanol are added at once.
  • the mixture is then cooled in an ice bath and still stirred for 1 hour.
  • the precipitate which forms is filtered off, washed with 10 ml_ of methanol and dried under vacuum at 40 0 C.
  • the product is recrystallized from a 3:1 (v/v) mixture of methanol and acetone. 6 g of levorotatory
  • EXAMPLE 7 Levorotatory (-)-1 -[(4-chlorophenyl)phenylmethyl]piperazine. 370 g (0.839 mol) of levorotatory (-)-1 -[(4-chlorophenyl)phenylmethyl]-4-[(4- methylphenyl)sulfonyl]piperazine (prepared in accordance with Example 3.A1 of U.S. Patent No. 5478941 ) and 405 g of 4-hydroxybenzoic acid are added to 1 liter of a 30% solution of hydrobromic acid in acetic acid. The suspension is stirred for 17 hours at 25 0 C. 2 liters of water are then added thereto and the suspension is cooled in an ice bath.
  • the precipitate which forms is filtered and washed with 750 mL of water. 2 liters of toluene and 0.9 liters of a 50 % aqueous solution of sodium hydroxide are then added to the filtrate. The organic phase is decanted off and washed with 100 mL of water and then once again with 1 liter of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent evaporated off under reduced pressure.
  • the residue is recrystallized from 600 ml_ of boiling hexane.
  • the solution is filtered while hot, so as to remove any slightly insoluble material and the filtrate is then allowed to crystallize, first at ambient temperature, and then for 24 hours in an ice bath.
  • the crystals are filtered off, washed with hexane and dried under vacuum at 40 0 C to afford 204.15 g of levorotatory (-)-1-[(4chlorophenyl) phenylmethyl]piperazine.

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Abstract

L'invention concerne des procédés de préparation de dichlorhydrate de lévocétirizine.
PCT/US2008/082802 2007-11-09 2008-11-07 Procédés de préparation de lévocétirizine et de ses sels pharmaceutiquement acceptables Ceased WO2009062036A2 (fr)

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IN2575CH2007 2007-11-09
IN2575/CHE/2007 2007-11-09
US5749608P 2008-05-30 2008-05-30
US61/057,496 2008-05-30

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2012101648A1 (fr) * 2011-01-24 2012-08-02 Havaldar Freddy H Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur
CN104045607A (zh) * 2014-05-21 2014-09-17 丽珠医药集团股份有限公司 一种盐酸西替利嗪的纯化方法
CN105954419A (zh) * 2016-06-01 2016-09-21 重庆华邦胜凯制药有限公司 Hplc法分离测定盐酸左西替利嗪及其对映异构体的方法
CN111205247A (zh) * 2020-04-22 2020-05-29 湖南九典宏阳制药有限公司 左旋西替利嗪的制备方法
CN117209453A (zh) * 2023-08-24 2023-12-12 迪嘉药业集团股份有限公司 一种盐酸左西替利嗪中间体的制备及应用

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CN106187920A (zh) * 2016-07-15 2016-12-07 苏州东瑞制药有限公司 一种盐酸左西替利嗪片的有关物质及其分析检测方法

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NO155805C (no) * 1981-02-06 1987-06-10 Ucb Sa Analogifremgangsmaate for fremstilling av terapeutisk virksomme 2-(4-(difenylmethyl)-1-piperazinyl)-eddiksyrer og deres amider og ikke-toksiske salter.
GB8827391D0 (en) * 1988-11-23 1988-12-29 Ucb Sa Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride
CA2180993A1 (fr) * 1996-07-11 1998-01-12 Yong Tao Methodes pour la preparation de cetirizine
US6384038B1 (en) * 1998-04-14 2002-05-07 Sepracor Inc. Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants
DK176706B1 (da) * 1999-03-04 2009-03-30 Sandoz As Fremgangsmåde til fremstilling af 2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}-eddikesyre-forbindelser eller salte deraf

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012101648A1 (fr) * 2011-01-24 2012-08-02 Havaldar Freddy H Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur
CN104045607A (zh) * 2014-05-21 2014-09-17 丽珠医药集团股份有限公司 一种盐酸西替利嗪的纯化方法
CN105954419A (zh) * 2016-06-01 2016-09-21 重庆华邦胜凯制药有限公司 Hplc法分离测定盐酸左西替利嗪及其对映异构体的方法
CN111205247A (zh) * 2020-04-22 2020-05-29 湖南九典宏阳制药有限公司 左旋西替利嗪的制备方法
CN111205247B (zh) * 2020-04-22 2020-08-14 湖南九典宏阳制药有限公司 左旋西替利嗪的制备方法
CN117209453A (zh) * 2023-08-24 2023-12-12 迪嘉药业集团股份有限公司 一种盐酸左西替利嗪中间体的制备及应用

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