WO2011073997A2 - Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers - Google Patents

Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers Download PDF

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WO2011073997A2
WO2011073997A2 PCT/IN2010/000794 IN2010000794W WO2011073997A2 WO 2011073997 A2 WO2011073997 A2 WO 2011073997A2 IN 2010000794 W IN2010000794 W IN 2010000794W WO 2011073997 A2 WO2011073997 A2 WO 2011073997A2
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hydroxy
methyl
pyrimidin
formula
pyrido
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WO2011073997A3 (fr
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Shriprakash Dhar Dwivedi
Dhimant Jasubhai Patel
Rushikesh Udaykumar Roy
Mayur Ramnikbhai Patel
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Zydus Lifesciences Ltd
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Cadila Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to improved processes for the preparation of paliperidone and pharmaceutically acceptable salts thereof.
  • the invention also relates to processes for the preparation of intermediates useful in the preparation of paliperidone and pharmaceutically acceptable salts thereof.
  • Paliperidone is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives and a racemic mixture having the structural Formula (I). Chemically, it is 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l -piperidyl]ethyl]-7-hydroxy- 4-methyl-l,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one,
  • Paliperidone is a metabolite of risperidone and is marketed under the trade name, Invega®. Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia. A process for the preparation of paliperidone is described in U.S. Patent No. 5, 158,952.
  • U.S. Patent No. 5,688,799 discloses a process for the synthesis of 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one.
  • U.S. Patent Publication No. 20070260061 discloses a process for preparing 9- hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one by reacting 2- amino-3-hydroxy pyridine with a slight excess of 2-acetyl-butyrolactone in an organic solvent such as 4-methyl-2-pentanol, a mixture of xylene and as 4-methyl-2-pentanol and chlorobenzene.
  • the condensation reaction involves the use of alcoholic solvents for the work-up stage. Further, the application relates to .
  • U.S. Patent Publication No. 20080214809 provides a process for the preparation of 9-hydroxy-3-(2-chloroyethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one and 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4- one. It discloses substantially isolated 9-hydroxy-3-(2-chloroyethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one containing less than about 26 ppm phosphorous.
  • PCT Publication No. WO 2008024415 discloses a process for the preparation of certain intermediates for the preparation of paliperidone. Further, it discloses two crystalline forms, viz. Form-I and Form-II of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one intermediate.
  • hydrochloride salt of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one which is in residue form is converted into a crystalline form of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one by using potassium acetate as the base and water for crystallization.
  • U.S. Patent Publication No. 2008/0171876 Al discloses a process for obtaining pure paliperidone by purification from various solvents. The process involves dissolution or suspension of paliperidone containing impurity in a solvent and isolation of pure paliperidone.
  • PCT Publication No. WO 2009/010988 Al discloses a process for purification of paliperidone via formation of paliperidone hydrochloride salt, which is further converted to paliperidone by treatment with a base.
  • the present inventors have found that there is no need to use mixture of organic solvents for the condensation reaction between 2-amino-3-hydroxy pyridine and 2- acetyl-butyrolactone and use of hazardous chemicals such as phosphorous oxychloride for the chlorination of the hydroxy intermediate.
  • the condensation reaction can be carried out in a single solvent system and using a safe reagent such as thionyl chloride for the chlorination.
  • a process for the preparation of paliperidone includes obtaining a solution or a suspension containing paliperidone; adding water and one or more halogenated solvents; separating the halogenated solvent layer containing paliperidone; additing a second solvent; optionally, removing the halogenated solvent; and isolating the paliperidone.
  • Embodiments of the process may include one or more of the following features.
  • the solution or suspension may be obtained by dissolving or suspending paliperidone in a suitable solvent.
  • a solution may be obtained directly from a reaction mixture in a process in which paliperidone is formed.
  • the solvent containing paliperidone may be heated to obtain a solution. It can be heated from about 30 °C to about reflux temperature of the solvent used, for example from about 30 °C to about 100 °C.
  • obtaining includes dissolving, slurrying, stirring or a combination thereof.
  • the isolation may include filtration, filtration under vacuum, centrifugation, and decantation.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the paliperidone obtained may be further purified by any process known in the art, which may optionally include crystallization and chromatographic purification.
  • any process known in the art which may optionally include crystallization and chromatographic purification.
  • (A) which is an intermediate in the preparation of paliperidone.
  • the process includes reacting 2-amino-3-hydroxy pyridine and 2-acetyl-butyrolactone in the presence of a substituted or unsubstituted aromatic hydrocarbon solvent and an acid catalyst.
  • the process may produce a crystalline form of 9-hydroxy-3-(2-hydroxyethyl)- 2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (A).
  • the process may produce a crystalline form of 9-hydroxyr3-(2-chloroethyl)-2- methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (B).
  • the process includes reacting 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one in an organic solvent in the presence of an acid.
  • the process may produce a crystalline form of the hydrochloride salt of 9- hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C).
  • the process includes hydrogenating the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one in an organic solvent with a suitable base.
  • the process may produce a crystalline form of 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydfoxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one, compound of Formula (D).
  • FIGURE 1 is an X-ray powder diffraction pattern of crystalline 9-hydroxy-3-(2- hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one.
  • FIGURE 2 is an X-ray powder diffraction pattern of crystalline 9-hydroxy-3-(2- chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one.
  • FIGURE 3 is an X-ray powder diffraction pattern of crystalline hydrochloride salt of
  • FIGURE 4 is an X-ray powder diffraction pattern of crystalline 3-(2-chloroethyl)-
  • the process includes:
  • the process includes reacting 2-amino-3- hydroxy-pyridine of Formula (II) with 2- acetylbutyro lactone of Formula (III) in the presence of an acid catalyst in a substituted or unsubstituted aromatic hydrocarbon solvent.
  • any acid catalyst which promotes the reaction can be used as a catalyst.
  • p-toluene sulfonic acid can be used as an acid catalyst.
  • the reaction can be carried out at ambient temperature to reflux temperature.
  • the reaction at step (i) may be carried out from about 100°C to about 160°C, for example at about 140- 145°C.
  • substituted or unsubstituted aromatic hydrocarbon solvents include toluene, xylene, chlorobenzene, ethyl benzene, 2,4-dichloro benzene, 4-chloro toluene and mixtures thereof.
  • Embodiments of the process may include one or more of the following features.
  • the 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin- 4-one of Formula (A) so obtained may be isolated using a suitable solvent.
  • a suitable solvent include one or more of dimethylformamide, dimethylsulfoxde, dimethylacetamide, sulfolane, N-methyl pyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C3-C6 ketones, or C3-C6 esters.
  • dimethylformamide may be used for the isolation of compound (A).
  • 2-amino-3- hydroxy-pyridine of Formula (II) may be reacted with 2- acetylbutyro lactone of Formula (III) in the presence of p-toluene sulfonic acid in xylene solvent at a reflux temperature.
  • Dimethylformamide may be further added to the reaction mass and the compound (A) may be isolated by cooling and filtration.
  • the process may produce crystalline form of 9-hydroxy-3-(2-hydroxyethyl)-2- methyi-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (A).
  • the crystalline form of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (A) may be characterized by X-ray diffraction peaks at 9.7, 10.8, 13.2, 16.2, 18.5, 20.6, 21.9, 22.2, 23.6, 26.0, 27.2, 27.8, 28.2, 29.8 and 32.6 degree two-theta, ⁇ 0.2 two-theta.
  • the process includes treating 9-hydroxy-3- (2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A) with a chlorinating agent to obtain 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one hydrochloride of Formula (C)
  • chlorinating agents examples include thionyl chloride, phosphorous pentachloride, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, and the like.
  • thionyl chloride may be used as a chlorinating agent
  • the chlorination reaction may be carried out in the presence of one or more organic solvents.
  • organic solvents examples include toluene, xylene, dichloromethane, trichloromethane, dimethylformamide, dimethylsulfoxide, sulfolane, and n-methyl pyrrolidone.
  • the process may produce a crystalline form of hydrochloride salt of 9-hydroxy- 3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (C).
  • the crystalline form of hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C) may be characterized by X-ray diffraction peaks at 7.8, 13.3, 14.5, 16.6, 17.9, 19.4, 22.6, 23.4, 24.9, 25.8, 26.1, 26.7, 27.0, 28.4, 29.3, 30.1, 30.5, 32.6, 35.7, 37.2 and 38.1 degree two- theta, ⁇ 0.2 two-theta.
  • 4- one hydrochloride of Formula (C) may be dissolved in water of one or more suitable organic solvents to obtain a solution.
  • the solution may be treated with ethylenediaminetetraacetate.
  • the solution may further be basified with one or more bases to obtain a free base of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one.
  • bases which may be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethyl amine, and diisopropyl amine.
  • sodium carbonate may be used as a base.
  • Embodiments of the process may include one or more of the following features.
  • the solution of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride in water may be treated with ethylenediaminetetraacetate and the solution may be filtered before treatment with a base. It may be further treated with sodium carbonate and the product may be isolated to provide 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B).
  • the process may produce a crystalline form of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B).
  • the crystalline form of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B) may be characterized by X-ray diffraction peaks at 5.2, 10.4, 1 1.9, 13.0, 14.2, 14.9, 15.8, 18.1, 18.9, 19.6, 20.4, 20.8, 21.5, 22.1, 22.5, 23.6, 24.6, 25.0, 25.6, 26.1, 26.7, 27.6, 28.6, 29.9, 31.0, 32.7, 33.4, 35.9, 36.7 and 37.2 degree two-theta, ⁇ 0.2 two-theta.
  • the crystalline form of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one, compound of Formula (B) may further be treated with hydrochloric acid in a suitable solvent or a solvent containing hydrogen chloride gas to obtain crystalline form of the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one, compound of Formula (C).
  • suitable solvents include one or more of Ci. 8 alcohols, C 3-7 esters, C 3-8 ethers, C 3-7 ketones, C6-i 2 aromatic hydrocarbons, acetonitrile, and water.
  • the crystalline form of hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C) may be characterized by X-ray diffraction peaks at 7.8, 13.3, 14.5, 16.6, 17.9, 19.4, 22.6, 23.4, 24.9, 25.8, 26.1 , 26.7, 27.0, 28.4, 29.3, 30.1, 30.5, 32.6, 35.7, 37.2 and 38.1 degree two- theta, ⁇ 0.2 two-theta.
  • 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H- pyrrido[l ,2-a]-pyrimidin-4-one compound of Formula (D) may be obtained by hydrogenating the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one in an organic solvent in the presence of a lewis acid; adding a suitable base to reaction mass; and crystallizing with a suitable solvent and isolating the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2- a]-pyrimidin-4-one.
  • the process may produce the crystalline form of 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one compound of Formula (D).
  • Examples of a suitable hydrogenating agent may include Pd/C, Pt/C, mixture of Pd/C and ZnCl 2 , and the like.
  • the preferred hydrogenating agent is mixture of Pd/C and ZnCl 2 .
  • Lewis acids include one or more of aluminum chloride, zinc chloride, ferric chloride, copper chloride, magnesium chloride.
  • a suitable organic solvent includes one or more of C1 -C5 alcohols.
  • methanol may be used as an organic solvent.
  • a suitable base examples include one or more of potassium acetate, sodium acetate, liquid ammonia, etc.
  • potassium acetate may be used as a base.
  • suitable solvents includes any solvent or solvent mixture in which paliperidone can be crystallized, including, for example, water, alcohols, ketones, and mixtures thereof. In particular, water may be used for crystallization.
  • Embodiments of the process may include one or more of the following features.
  • the solution or suspension may be obtained by dissolving or suspending paliperidone in a suitable solvent.
  • such a solution may be obtained directly from a reaction mixture in a process in which paliperidone is formed.
  • 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]-pyrimidin-4-one may be reacted with 6-fluoro-3-(piperidinyl)-l ,2- benzisooxazole of Formula (F) in a first organic solvent in the presence of a base to obtain a reaction mass containing paliperidone.
  • water and one or more halogenated solvents may be added and the halogenated solvent layer containing paliperidone may be separated.
  • a second solvent may be added and halogenated solvent may be removed by distillation.
  • the reaction mass may be cooled to crystallize paliperidone, filtered and isolated by conventional techniques.
  • organic solvents examples include one or more of C] -8 alcohols, C3-7 esters,
  • C 3- ethers C3.7 ketones, C 6 -i 2 aromatic hydrocarbons, acetonitrile, halogenated solvent, C 3- 6 ketones, a mixture of a C 3 - 6 ketone and water, N-methylpyrrolidone, C 3-6 amides, dimethylsulfoxide.
  • methanol may be used as a solvent.
  • the reaction may preferably be carried out in the presence of a base in an organic solvent.
  • the base which can be used in the condensation step may be selected from an inorganic base or an organic base
  • the inorganic bases may include hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide.
  • the organic bases may include triethyl amine, di-isopropyl amine, diisopropyl ethyl amine and the like. In particular, diisopropyl ethyl amine is used as a base.
  • the reaction can be carried out in the presence of a catalyst.
  • a catalyst can be potassium iodide, sodium iodide, phase transfer catalyst like quaternary ammonium salts like benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride and domiphen bromide and the like. More particularly, potassium iodide is used as a catalyst.
  • halogenated solvent can be selected from methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, chloro benzene etc. In particular, methylene dichloride is used.
  • Second solvent can be selected from C 3-6 ketones, a mixture of a C 3- 6 ketone and water, N-methylpyrrolidone, C 3-6 amides, propylene glycol, dimethyl sulfoxide, dimethyl carbonate, C 1 .4 alkyl alcohols, a mixture of a alkyl alcohol and water, acetonitrile, a mixture of acetonitrile and water, C 2-6 alkyl acetates, a mixture of a C 2 . 6 alkyl acetate and water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C 2-8 ethers.
  • Examples of C3-6 ketones include acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK).
  • Examples of C 3- 6 amides include dimethylacetamide and dimethylformamide.
  • Examples of C 1-4 alkyl alcohols include methanol, ethanol, n- propanpl, isopropanol, n-butanol, isobutanol and 2-butanol.
  • Examples of C 2- 6 alkyl acetates include ethyl acetate, isopropyl acetate and isobutyl acetate.
  • Examples of C 2-8 ethers include diethyl ether, methyl tet-butyl ether, dibutyl ether and polyethylene glycol (PGME). More particularly, a mixture of acetone and water is used as a solvent.
  • reaction mass was cooled to 95°C to 100°C and dimethylformamide was added. Further, the reaction mass was cooled to 0°C to 5°C and washed with xylene to afford the title compound as crystalline 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one, compound of Formula (A) (HPLC Purity: 98.80%)
  • dichloromethane was distilled out and again dichloromethane (400 mL) was added at 39°C to 45 °C and distilled out at atmospheric pressure at 38°C to 43°C.
  • the reaction mass was degassed for 2 hours under vacuum below 60°C.
  • the reaction mass was cooled to 35°C to 40°C and water (300 mL).
  • HP-120 charcoal (10 g) was added and stirred for 1 hour at 35°C to 40°C.
  • Example 3 Preparation of crystalline 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (B) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one
  • Example 4 Preparation of crystalline hydrochloride salt of 9-hydroxy-3-(2- chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (C) 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one (100 g) and methanol (800 mL) were added and heated at 60°C to 65°C to get a clear solution and maintained for 30 mins. To the reaction mass, dry IPA/HC1 (95 g) was added to get a pH of 1 to 3.
  • the reaction mass was cooled to 25°C to 35°C, filtered and washed with methanol (2 x 100 mL).
  • the total methanol mother liquor obtained was treated with HP-120 charcoal (15 g) at 25°C to 35°C.
  • the reaction mass was heated to 50°C to 55°C for 30 min.
  • the reaction mass was filtered and washed with methanol (2 x 100 mL).
  • Methanol was distilled out completely under vacuum below 65°C.
  • the reaction mass was degassed for 2 hours under vacuum below 75°C. Water (365 mL) was added at 70°C to 75°C and stirred for 30 min.
  • the reaction mass was cooled to 25°C to 35°C and potassium acetate solution (35.0 g potassium acetate + 375.0 ml water) was added within 1 to 1.5 hours and stirred for 30 min. Further, sodium carbonate solution (25.0 g sodium carbonate + 375.0 ml water) was added and stirred for 1 hour at 25°C to 35°C. The reaction mass was filtered and washed with water (2 x 50 mL) to afford the title compound as crystalline 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one compound of Formula (D) (HPLC purity 96.7%).

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne le procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables, ledit procédé de préparation consistant à: (a) condenser du 2-amino-3-hydroxy- pyridine avec du 2-acétylbutyro lactone en présence d'un catalyseur acide afin d'isoler le 9- hydroxy-3-(2-hydroxyéthyl)-2-méthyl-4H-pyrido[l, 2-a] pyrimidin-4-one; traiter le 9- hydroxy-3-(2-hydroxyéthyl)-2-éthyl-4H-pyrido[l, 2-a] pyrimidin-4-one avec un agent de chloration; hydrogéner le produit en présence d'au moins un acide de Lewis pour obtenir du 3-(2-chloroéthyl)-6,7,8,9-tétrahydro-9-hydroxy-2-méthyl-4H-pyrrido[l,2-a]- pyrimidin-4-one; et condenser le 3-(2-chloroéthyl)-6,7,8,9-tétrahydro-9-hydroxy-2- méthyl-4H-pyrrido[l,2-a]-pyrimidin-4-one. La présente invention concerne également des procédés de préparation d'intermédiaires utiles dans la préparation de palipéridone et de ses sels pharmaceutiquement acceptables.
PCT/IN2010/000794 2009-12-14 2010-12-08 Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers Ceased WO2011073997A2 (fr)

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Cited By (3)

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WO2015007191A1 (fr) * 2013-07-16 2015-01-22 江苏恩华药业股份有限公司 Dérivés d'acides aminés de palipéridone et leurs utilisation
CN104502466A (zh) * 2014-11-20 2015-04-08 美吉斯制药（厦门）有限公司 一种用液相色谱法分离测定帕潘立酮原料及其制剂的方法
CN104557915A (zh) * 2014-12-01 2015-04-29 浙江京新药业股份有限公司 制备高纯度帕利哌酮ii晶型的方法

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