WO2012035554A1 - Procédé amélioré de préparation de palipéridone très pure - Google Patents

Procédé amélioré de préparation de palipéridone très pure Download PDF

Info

Publication number
WO2012035554A1
WO2012035554A1 PCT/IN2011/000626 IN2011000626W WO2012035554A1 WO 2012035554 A1 WO2012035554 A1 WO 2012035554A1 IN 2011000626 W IN2011000626 W IN 2011000626W WO 2012035554 A1 WO2012035554 A1 WO 2012035554A1
Authority
WO
WIPO (PCT)
Prior art keywords
paliperidone
solvent
base
pure
crude
Prior art date
Application number
PCT/IN2011/000626
Other languages
English (en)
Inventor
Vijayavitthal Thippannachar Mathad
Pavankumar Vrajlal Solanki
Babu Uppelli Sekhar
Bhushan Sudhakar Pandit
Original Assignee
Megafine Pharma (P) Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Megafine Pharma (P) Ltd. filed Critical Megafine Pharma (P) Ltd.
Publication of WO2012035554A1 publication Critical patent/WO2012035554A1/fr

Links

Classifications

    • 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 an improved process for the preparation of highly pure paliperidone of formula-I;
  • the present invention relates to the production friendly process for the preparation of highly pure paliperidone substantially free from impurity namely, keto-paliperidone.
  • the present invention relates to the process for the preparation of highly pure paliperidone having particle size below 60 microns which can be directly obtained by crystallization without any further processing steps.
  • Paliperidone (sold as INVEGA, INVEGA Sustenna), also known as 9-hydroxyrisperidone, is an atypical antipsychotic. Chemically, paliperidone is the primary active metabolite of the older atypical antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone, i.e. risperidone with an extra hydroxyl group). It is indicated for the acute and maintenance treatment of schizophrenia.
  • Paliperidone chemically known as (3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl]ethyl]6,7,8,9-tetra-hydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one) and has the following structural formula-I.
  • US 4,804,663 and US 5,158,952 describe processes for the preparation of 3-piperidinyl-l,2- benzisoxazole derivatives along with their pharmaceutical compositions and methods of use.
  • the processes for synthesizing paliperidone and related compounds are disclosed in US 5,158,952; US 5,254,556 and US 5,688,799.
  • the activating reagent includes halogenating reagent such as, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, and thionyl chloride.
  • halogenating reagent such as, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, and thionyl chloride.
  • the reaction mass is extracted with trichloromethane and then subjected to chromatographic purifications using chloroform and methanol and further recrystallized from isopropanol.
  • the chromatographic purification process is not commercially viable. The process results in formation of significant impurities due to the reaction of compound of formula (II) with the compound of formula (V).
  • the compound of formula (III) is further reduced to 3-(2-chloroethyl)-9-hydroxy-2-methyl- 6,7,8,9-tetrahydro-4H-pyrido[l,2-a]-pyrimidin-4-one of formula (IV) by using palladium on carbon as a catalyst and in presence of methanol, which is further condensed with 6-fluoro-3- piperidin-4-yl-l ,2-benzisoxazole hydrochloride of formula (VI) in presence of phase transfer catalyst to yield paliperidone of formula-I.
  • Paliperidone obtained by the process of '952 patent does not have satisfactory purity for pharmaceutical use. Unacceptable amount of impurities are generally formed along with the paliperidone.
  • the process involves the additional step of column chromatographic purifications. Methods involving column chromatographic purification are generally undesirable for large-scale operations thereby making the process commercially unfeasible and inefficient.
  • paliperidone Like any synthetic compound, paliperidone contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products of side reaction, and/or degradation products. To meet the regulatory quality norms, identification, isolation, synthesis and characterization of the impurities followed by their control to the ICH levels in the final drug compound is a must.
  • a number of purification processes for the purification of paliperidone are available in the art but each one has its own drawback.
  • Many of purification processes known in the art makes use of reducing agents in order to control the keto-paliperidone or multiple number of purification process with a huge volume of solvent (60 to 80 volumes of solvent per gram of crude paliperidone), which make process in-efficient as huge amount of solvent is required and very big reactors are required to fullfil the process requirements, and this in turn restricts the batch size in the production.
  • Another drawback is related to overall yield of paliperidone obtained which is very less resulting in extremely high cost and low throughput.
  • the paliperidone is dissolved in suitable alcoholic solvent (50 to 70 times), the solution is treated with the reducing agent and the solution obtained is partially concentrated to get the pure paliperidone as a crystalline solid which is filtered and dried to yield 50 to 55 % of product having lesser amount of keto-paliperidone.
  • An object of the invention is to provide an improved process for the preparation of paliperidone which is a simple, efficient, production friendly, commercially viable and economical process.
  • Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone which is substantially free from impurity namely, keto-paliperidone.
  • Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone with good yield and quality.
  • Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone without use of any reducing agent for controlling impurity namely, keto- paliperidone.
  • Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone where the process is simple, efficient, production friendly, commercially viable and economical as it does not involve huge quantity of solvent volumes thus reducing the effluents and increasing the through-put.
  • Yet another object of the present invention is to provide an improved process for the preparation of pharmaceutically acceptable paliperidone of formula-I where paliperidone is obtained having particle size below 60 microns by simple crystallization techniques.
  • step (b) of the invention further comprising suspending the wet material obtained from the step (b) in a base and heating the mixture optionally under reduced pressure; filtering and drying the wet product under vacuum to obtain pure paliperidone.
  • the solvent used in step (a) is selected from group comprising of toluene, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, ethylene chloride, diglyme, cyclohexane, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide or Cj to C 6 straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol, or mixture thereof.
  • the solvent used in step (a) is selected from methanol, acetonitrile, acetone, isoprbpyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. More preferably, the solvent used in step (a) is selected from acetonitrile or methanol.
  • the base used in step (a) is either organic base or inorganic base.
  • the inorganic base is selected from group comprising of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and like.
  • the organic base is selected from diisopropyl ethyl amine, di-isopropyl amine, pyridine, triethyl amine and the like.
  • the base used in step (a) is potassium carbonate or di-isopropyl amine.
  • the catalyst used in step (a) is selected from organic or inorganic catalyst.
  • the organic catalyst is selected from l,8-Diazabicycloundec-7-ene (DBU) or 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the organic catalyst used in step (a) is l,8-Diazabicycloundec-7-ene (DBU).
  • the inorganic catalyst is selected from groups comprising alkali, metal iodide such as but not limited to sodium iodide, potassium iodide, lithium iodide and the like.
  • the alkali metal iodide used in step (a) is potassium iodide.
  • the time required for completion of the reaction of step (a) is from 5 to 60 hours; preferably, from 20 to 50 hours; more preferably, from 30 to 40 hours.
  • the crude paliperidone is isolated from the reaction mass of step (a) by cooling the reaction mass to precipitate out the solid, filtering the solid containing inorganic salts, treating the solid with water and filtering and drying the crude paliperidone which is free of inorganic salts.
  • the crude paliperidone is optionally dried under vacuum at 50°C to 60°C till constant weight is achieved.
  • the crude paliperidone is isolated from the reaction mass of step (a) by cooling the reaction mass to precipitate out the solid, filtering the solid containing inorganic salts, treating the solid with water and water immiscible organic solvent, separating the organic phase containing paliperidone from the aqueous phase, optionally washing the organic phase with alkaline water and distilling out the solvent from the organic phase to obtain the crude paliperidone which is directly used for purification step (b).
  • the crude paliperidone is isolated from the reaction mass of step (a) by distilling out the solvent followed by adding the water and water immiscible organic solvent to the residue, separating the organic phase containing paliperidone from the aqueous phase, optionally washing the organic phase with alkaline water and distilling out the solvent from the organic phase to obtain the crude Paliperidone which is directly used for purification step (b).
  • the alkaline water used for washing the organic phase containing paliperidone is selected from solution of alkali metal hydroxides, solution of alkali metal carbonates, alkali metal bicarbonate or ammonia or the like.
  • the water-immiscible solvent used for the isolation of paliperidone is selected from group comprising chlorinated hydrocarbons such as methylene chloride, ethylene chloride, trichloromethane and carbon tetrachloride and the like.
  • the water-immiscible solvent used for the isolation of paliperidone is methylene chloride.
  • the solvent used in step (b) is selected from group comprising C 3 to C 6 ketone, N- methylpyrrolidone, C 3 to C 6 amides, propylene glycol, dimethylsulfoxide, Cj to C 6 straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol or mixture thereof, acetonitrile, alkyl acetates, C 2 to C 8 ethers including tetrahydrofuran, 2-methyl tertahydrofuran and the likes.
  • the solvent used in step (b) is selected from acetone, isopropyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. More preferably, the solvent used in step (b) is tetrahydrofuran.
  • the crude paliperidone is treated with solvent in presence of base at temperature ranging from 40°C to 80°C to obtain clear solution which is cooled to crystallize out pure paliperidone.
  • the crude paliperidone is treated with solvent in presence of base at temperature ranging from 50°C to 70°C.
  • the clear solution obtained in step (b) is then gradually cooled to temperature ranging from 0° to 30°C; preferably 0° to 10°C; most preferably 0° to 5°C for crystallizing out the pure paliperidone.
  • the base used in the purification step (b) is selected from inorganic base such as liquor ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like or organic base such as diethyl amine, triethyl amine, diisopropyl amine, and the like.
  • the base used in the purification step (b) is liquor ammonia.
  • the concentration of ammonia is ranging from 1 to 30 weight percent; preferably 4 to 15 weight%, more preferably 4 to 7 weight%.
  • the purification step (b) is carried out at pH ranging from 6 to 14; preferably from 8 to 10.
  • the step (b) of the invention further optionally comprising suspending the wet material obtained from the step (b) in 4 to 7 % of liquor ammonia and heating the mixture at temperature ranging from 30°C to 80°C; preferably 50°C to 70°C optionally under reduced pressure; filtering and drying the wet product under vacuum to obtain pure paliperidone.
  • the pure paliperidone is dried at temperature ranging from 40 to 100°C, preferably at temperature ranging from 50°C to 80°C under vacuum.
  • yield of pure paliperidone is in the range of 80 to 85 % and is substantially free from keto-paliperidone impurity.
  • the pure paliperidone obtained has particle size d (0.50) below 60 micron and can be directly used for formulation, therefore does not require separate process to reduce particle size which is acceptable / required for formulation.
  • the pure dried crystallized paliperidone is further optionally purified by suspending or dissolving the pure dried crystallized paliperidone in a mixture of solvent and base at a temperature ranging from 30°C to 80°C followed by cooling the suspension and filtering and drying the wet product at temperature ranging from 40°C to 100°C under vacuum to obtain pure paliperidone.
  • the solvent used for further purifying the dried crystallized paliperidone is selected from group comprising C 3 to C 6 ketone, N-methylpyrrolidone, C 3 to C 6 amides, propylene glycol, dimethylsulfoxide, Q to C 6 straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol or mixture thereof, acetonitrile, alkyl acetates, C 2 to C ethers including tetrahydrofuran, 2-methyl tetrahydrofuran and the like.
  • the solvent is selected from acetone, isopropyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. Most preferably, the solvent is acetone.
  • the base used for further purifying the pure dried crystallized paliperidone is selected from inorganic base like liquor ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like or organic base like, diethyl amine, triethyl amine, diisopropyl amine and the like.
  • the bass is liquor ammonia.
  • the purity of Paliperidone obtained according to the invention is at least 99.85%.
  • the pure paliperidone obtained by further purification of pure dried crystallized paliperidone has particle size d (0.50) below 40 micron and can be directly used for formulation, therefore do not require separate process to reduce particle size which is acceptable / required for formulation.
  • d 0.50
  • the use of liquor ammonia in combination with suitable solvent during the crystallization of paliperidone drastically reduces impurity, namely the keto paliperidone in a single crystallization step with higher yield of around 80% to 85%, which otherwise requires multiple crystallization and huge amount of solvent quantity (50 to 70 parts per part of paliperidone).
  • the present invention eliminates multiple crystallization thereby reduces consumption of solvent and hence reduces generation of effluents. Multiple crystallization reduce yield to 50 to 55%.
  • the present invention eliminates multiple crystallization, use of huge amount of solvent and improves yield.
  • the second advantage of using base in combination with suitable solvent is to increase the dissolution of paliperidone for crystallization process, thereby requiring minimum dissolution volume (9.5 - 1 1 parts per part of crude paliperidone) for crystallization process, which increases the efficiency of process, thereby reducing the cost and increasing throughput of the process.
  • the third advantage of the developed process is to obtain the desired particle size during the purification and hence eliminating separate process to reduce particle size which is required for formulation.
  • Paliperidone obtained according to the invention has particle size below 60 microns, preferably below 40 microns by simple crystallization techniques.
  • Example 1 The present invention is illustrated by the following examples, which is not intended to limit the effective scope of the invention.
  • Example 1
  • the cake obtained was washed with 1.0 L of acetonitrile.
  • Weight of wet product containging paliperidone and inorganic salts was 3.70 kg, HPLC purity of paliperidone: 97.50%, keto-paliperidone impurity: 0.44%.
  • the wet product obtained was further used for purification process.
  • the cake obtained was washed with 0.5 L of chilled methanol.
  • Weight of wet product containing paliperidone and inorganic salts was 1.0 kg, HPLC purity of paliperidone: 98.88%, keto- paliperidone impurity: 0.05%.
  • the wet product obtained was further used for purification process.
  • Weight of wet product containing paliperidone was 1.9 kg, HPLC purity of paliperidone: 96.18%, keto-paliperidone impurity: 0.05%.
  • the wet product obtained was dried at 50-55°C and further used for purification process.
  • the reaction mass was cooled to 25-30°C and further chilled to 15-20°C, stirred for 60 min. and centrifuged.
  • the cake obtained was washed with 0.5 L of chilled methanol.
  • Weight of wet product containing paliperidone was 1.9 kg, HPLC purity of paliperidone: 97.15%, keto-paliperidone impurity: 0.30%.
  • the wet product obtained was obtained was dried at 50-55°C and further used for purification process.
  • Example 6 The wet product obtained in Example- 1 was suspended in purified water (15.0 L) and the mixture was heated to 70-80°C and maintained for 60 min. The reaction mass was then hot filtered and the cake was washed with purified water (1.0 L). The wet material was dried under vacuum at 50-60°C till constant weight was achieved. Yield of paliperidone: 1.50 kg; HPLC purity of paliperidone: 98.5%; keto paliperidone impurity: 0.65 % by HPLC. Example 6
  • Example-2 The wet product obtained in Example-2 was suspended in purified water (10.0 L) and the mixture was heated to 70-80°C and maintained for 60 min. The reaction mass was then hot filtered and the cake was washed with purified water (1.0 L). The wet material was dried under vacuum at 50-60°C till constant weight was achieved. Yield of paliperidone: 0.90 kg; HPLC purity of paliperidone: 98.78%; keto paliperidone impurity: 0.06 % by HPLC.
  • Example 7 The ruggedness of the experiment (Example-7) has been established by performing the experiments with crude paliperidone containing the varied percentage of keto-paliperidone in it. The content of keto-paliperidone impurity was monitored before and after purification and the results obtained are given in Table 1.
  • Table-I Experimental evidence for the Elimination of keto-paliperidone using THF-Liquid ammonia along with the PSD data of the obtained paliperidone.
  • the crude paliperidone obtained was treated with tetrahydrofuran (1 1.55 L), and liquor ammonia (4.95 L), heated to reflux temperature to obtain clear solution and maintained for 60 min.
  • the reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min.
  • the precipitate obtained was filtered and washed with purified water (1.5 L).
  • Weight of wet product 2.8 kg.
  • Wet product (2.8 kg) obtained was treated with liquor ammonia (18 L) and the mixture was heated to 60°C -65°C for 2 hours.
  • the reaction mass was then hot filtered, wet cake obtained was washed with purified water (2.4 L) and dried under vacuum at 70°-75°C till constant weight was achieved.
  • the crude paliperidone obtained was treated with tetrahydrofuran (6.93 L), and liquor ammonia (2.97 L), heated to reflux temperature to obtain clear solution and maintained for 60 min.
  • the reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min.
  • the crude paliperidone obtained was treated with tetrahydrofuran 8.47L), and liquor ammonia (3.63L), heated to reflux temperature to obtain clear solution and maintained for 60 min.
  • the reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min.
  • Table-2 PSD data of paliperidone before and after acetone-ammonia treatment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation de palipéridone pure sensiblement exempte d'impuretés, à savoir de cétopalipéridone. 3-(2-chloroéthyl)-9-hydroxy-2-méthyl-6,7,8,9-tétrahydro- 4H-pyrido[1,2-a]-pyrimidin-4-one est condensée avec de l'hydrochlorure de 6-fluoro-3-pipéridin-4-yl-1,2- benzisoxazole ou un sel de celui-ci en présence d'un solvant, d'une base et d'un catalyseur en vue de l'obtention de palipéridone brute. La palipéridone brute est purifiée par traitement de celle-ci au moyen d'un solvant en présence d'une base à une température de reflux, en vue de l'obtention d'une solution claire qui est refroidie afin que de la palipéridone pure soit produite par cristallisation.
PCT/IN2011/000626 2010-09-14 2011-09-13 Procédé amélioré de préparation de palipéridone très pure WO2012035554A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2543MU2010 2010-09-14
IN2543/MUM/2010 2010-09-14
IN2120/MUM/2011 2011-07-26
IN2120MU2011 2011-07-26

Publications (1)

Publication Number Publication Date
WO2012035554A1 true WO2012035554A1 (fr) 2012-03-22

Family

ID=45446142

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000626 WO2012035554A1 (fr) 2010-09-14 2011-09-13 Procédé amélioré de préparation de palipéridone très pure

Country Status (1)

Country Link
WO (1) WO2012035554A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
EP0368388A2 (fr) * 1988-11-07 1990-05-16 Janssen Pharmaceutica N.V. 3-Pipéridinyl-1,2-benzisoxazoles
US5158952A (en) 1988-11-07 1992-10-27 Janssen Pharmaceutica N.V. 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
US5254556A (en) 1988-11-07 1993-10-19 Janssen Pharmaceutica N.V. 3-piperidinyl-1,2-benzisoxazoles
US5688799A (en) 1993-11-23 1997-11-18 Janssen Pharmaceutica N.V. 9-Hydroxy-pyrido 1,2-a!pyrimidin-4-one ether derivatives
US20080171876A1 (en) 2007-05-10 2008-07-17 Santiago Ini Pure paliperidone and processes for preparing thereof
WO2009116071A2 (fr) * 2008-02-05 2009-09-24 Watson Pharma Private Limited Procédé amélioré pour la préparation de palipéridone
WO2009118655A2 (fr) * 2008-03-27 2009-10-01 Actavis Group Ptc Ehf Palipéridone de haute pureté ou sel pharmaceutiquement acceptable de celle-ci sensiblement exempte d’impureté céto
WO2010003703A2 (fr) * 2008-07-11 2010-01-14 Synthon B.V. Palipéridone cétone
WO2010004578A2 (fr) * 2008-06-16 2010-01-14 Msn Laboratories Limited Nouveaux procédés améliorés de préparation de la palipéridone
WO2010089643A1 (fr) * 2009-02-03 2010-08-12 Cadila Pharmaceuticals Ltd. Procédé amélioré de préparation de la palipéridone
EP2275423A1 (fr) * 2009-07-13 2011-01-19 Krka Procédé de synthèse de palipéridone

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
EP0368388A2 (fr) * 1988-11-07 1990-05-16 Janssen Pharmaceutica N.V. 3-Pipéridinyl-1,2-benzisoxazoles
US5158952A (en) 1988-11-07 1992-10-27 Janssen Pharmaceutica N.V. 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
US5254556A (en) 1988-11-07 1993-10-19 Janssen Pharmaceutica N.V. 3-piperidinyl-1,2-benzisoxazoles
US5688799A (en) 1993-11-23 1997-11-18 Janssen Pharmaceutica N.V. 9-Hydroxy-pyrido 1,2-a!pyrimidin-4-one ether derivatives
US20080281100A1 (en) 2007-05-10 2008-11-13 Santiago Ini Pure paliperidone and processes for preparing thereof
US20080171876A1 (en) 2007-05-10 2008-07-17 Santiago Ini Pure paliperidone and processes for preparing thereof
WO2008140641A2 (fr) * 2007-05-10 2008-11-20 Teva Pharmaceutical Industries Ltd. Palipéridone pure et ses procédés de préparation
WO2009116071A2 (fr) * 2008-02-05 2009-09-24 Watson Pharma Private Limited Procédé amélioré pour la préparation de palipéridone
WO2009118655A2 (fr) * 2008-03-27 2009-10-01 Actavis Group Ptc Ehf Palipéridone de haute pureté ou sel pharmaceutiquement acceptable de celle-ci sensiblement exempte d’impureté céto
US20090247553A1 (en) 2008-03-27 2009-10-01 Actavis Group Ptc Ehf Highly Pure Paliperidone or a Pharmaceutically Acceptable Salt Thereof Substantially Free of Keto Impurity
WO2010004578A2 (fr) * 2008-06-16 2010-01-14 Msn Laboratories Limited Nouveaux procédés améliorés de préparation de la palipéridone
WO2010003703A2 (fr) * 2008-07-11 2010-01-14 Synthon B.V. Palipéridone cétone
WO2010089643A1 (fr) * 2009-02-03 2010-08-12 Cadila Pharmaceuticals Ltd. Procédé amélioré de préparation de la palipéridone
EP2275423A1 (fr) * 2009-07-13 2011-01-19 Krka Procédé de synthèse de palipéridone

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104502466B (zh) * 2014-11-20 2021-01-26 万全万特制药（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

Similar Documents

Publication Publication Date Title
RU2683566C1 (ru) Производное с сочлененными кольцами и способ его получения, промежуточное соединение, фармацевтическая композиция и их применение
US20100261908A1 (en) Processes for the preparation of prasugrel , and its salts and polymorphs
EP3077375B1 (fr) Procédé pour la production de 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1h-indole dimesylate monohydrate à grande échelle
US20090048272A1 (en) Preparation of paliperidone
WO2009010988A1 (fr) Procédé amélioré, industriellement viable pour la préparation de palipéridone de haute pureté
WO2011067220A1 (fr) Procede de purification de paliperidone
US20100311969A1 (en) Process For Preparation of Paliperidone
WO2006027370A1 (fr) Preparation de 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4h-pyrido`1,2-a!pyrimidin-4-one et leurs cristaux
WO2010004578A2 (fr) Nouveaux procédés améliorés de préparation de la palipéridone
WO2009044413A2 (fr) Procédé amélioré de préparation de palipéridone, nouvelles formes polymorphes et procédé associés
EP2235009B1 (fr) Synthèse de palipéridone
EP2202234A1 (fr) Purification de la palipéridone
CZ300692B6 (cs) Zpusob prípravy solifenacinu
WO2012035554A1 (fr) Procédé amélioré de préparation de palipéridone très pure
CN112062763B (zh) 羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物及制备和应用
CN104250251B (zh) 一种替格瑞洛的制备方法
WO2010122575A2 (fr) Procédé de préparation de palipéridone pure
EA011748B1 (ru) Способ получения рисперидона
WO2011073997A2 (fr) Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers
KR101867988B1 (ko) 팔리페리돈 중간체 및 이를 이용한 팔리페리돈의 제조방법
EP2382213B1 (fr) Processus en une étape pour préparer la palipéridone et son sel oxalate
US20120165527A1 (en) process for the preparation of pure paliperidone
US20060004199A1 (en) Process for the preparation of pure 3-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
WO2012042368A1 (fr) Procédé de préparation de palipéridone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11805240

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11805240

Country of ref document: EP

Kind code of ref document: A1