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WO2012042368A1 - Procédé de préparation de palipéridone - Google Patents

Procédé de préparation de palipéridone Download PDF

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Publication number
WO2012042368A1
WO2012042368A1 PCT/IB2011/002312 IB2011002312W WO2012042368A1 WO 2012042368 A1 WO2012042368 A1 WO 2012042368A1 IB 2011002312 W IB2011002312 W IB 2011002312W WO 2012042368 A1 WO2012042368 A1 WO 2012042368A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
hydroxy
methyl
pyrimidin
pyrido
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2011/002312
Other languages
English (en)
Inventor
Sailaja Vundela
Sayyed Asif Parvez
Nagaji Ambabhai Vekariya
Aminul Islam
Meenakshisunderam Sivakumaran
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma 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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2012042368A1 publication Critical patent/WO2012042368A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 pure
  • Paliperidone is chemically known as, 9(RS)-3-[2-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)- 1 -piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]- pyrimidin-4-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.
  • the reaction mixture containing paliperidone obtained according to the method of US '952 patent is subjected to evaporation and the oily residue is extracted with trichloromethane followed by water washings. The organic layer is dried, filtered and evaporated followed by column chromatographic purifications over silica gel using a mixture of trichloromethane and methanol. The pure fractions are collected and the eluent is evaporated. The resulting residue is crystallized from 2-propanone. After cooling, the precipitated product is filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane, and recrystallized from 2-propanol to produce paliperidone.
  • Paliperidone obtained by this process does not have satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities were formed along with paliperidone.
  • the process involves the additional step of column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large scale operations, thereby making the process commercially unfeasible.
  • WO 2008/021346 discloses various methods for the purification of paliperidone, which are as given below.
  • a solvent selected from the group consisting of C 3- ketone or a mixture thereof with water, N- methyl
  • the present inventors have repeated the above process, and found that the final drug substance obtained by above process contains about 1.12% of diketo compound of Formula XI,
  • the main objective of the present invention is to provide a simple and cost effective process for the preparation of pure Paliperidone.
  • Another objective of the present invention is to provide a process for the preparation of Paliperidone, which is simple, industrially applicable and economically viable.
  • Yet another objective of the present invention is to provide a process for the preparation of Paliperidone with improved color and which contain diketo compound less than 0.1%.
  • the present invention relates to an improved process for the preparation Paliperidone of Formula 1,
  • step (e) condensing the product obtained in step (e) with 6-fluoro-3-piperidino-l,2- benzisoxazol hydrochloride of Formula VI,
  • the present invention relates to a process for preparing 3-(2- chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X,
  • the present invention relates to a process for purifying Paliperi done of Formula I, which comprises: .
  • the present invention relates to an improved process for the preparation of Paliperidone, which comprises purifying the 3-(2-chloroethyl)-9-hydroxy-2-methyl- 4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X, by dissolving in solvent selected from methanol and adding anti-solvent selected from diisopropylether to give 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X.
  • the hydrogenation of compound of Formula X is carried out using catalyst in methanol to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[l ,2-a]pyrimidin-4-one of Formula V, which is isolated from water and purified by dissolving in mixture of acetone and cyclohexane and silica gel treatment followed by concentration to obtain a residue.
  • the catalyst used for hydrogenation is selected from Palladium, Platinum or Raney Nickel.
  • the present invention relates to a process for preparing 3-(2- chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X, which comprises reacting 2-amino-3 -hydroxy pyridine of Formula VIII with 3-acetyl-4,5-dihydro-3H-2-furanone of Formula III to give 3-(2-hydroxyethyl)-9- hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one of Formula IX, followed by chlorination to give compound of Formula X.
  • the condensation of compound of Formula VIII with compound of Formula IX is carried out in the presence of acid selected from hydrochloric acid, sulfuric acid, benzenesulfonic acid and p-toluenesulfonic acid and solvent selected from toluene, xylene, chlorobenzene and mixture thereof, at a temperature in the range of 120- 150°C.
  • acid selected from hydrochloric acid, sulfuric acid, benzenesulfonic acid and p-toluenesulfonic acid and solvent selected from toluene, xylene, chlorobenzene and mixture thereof, at a temperature in the range of 120- 150°C.
  • the chlorination of compound of formula IX is carried out using a chlorinating agent selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, in the presence of dimethylformamide to give compound of Formula X.
  • a chlorinating agent selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, in the presence of dimethylformamide to give compound of Formula X.
  • the Paliperidone obtained by the present invention is in crystalline form.
  • the present invention provides purification methods for obtaining highly pure Paliperidone of Formula I.
  • Method - 1 provides purification methods for obtaining highly pure Paliperidone of Formula I.
  • the purification process comprises:
  • the purification process comprises:
  • the purification process comprises:
  • the base is selected from organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-diisopropylethylamine and mixtures thereof and more preferably triethylamine and the solvent is selected from solvent consisting of C 3-7 branched or chained hydrocarbons, C 2-7 chained or branched ethers, cyclic ethers, lower fatty acid esters, aliphatic ketone solvents, halogenated hydrocarbon solvents or nitrile solvents and mixture there of; isolation is carried by crystallization or precipitating by adding anti-solvents in which product is poorly soluble selected from the same group of solvents as mentioned above or by crystallization after removing of partial solvents.
  • organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-diisopropylethylamine and mixtures thereof and more preferably triethylamine
  • the paliperidone obtained according to above process has an improved color and contains diketo compound of Formula XI less than 0.1 % of total drug substance.
  • 6-Fluoro-3-piperidino-l ,2-benzisoxazol hydrochloride (36.46 g) was suspended into methanol (300 ml), followed by addition of triethylamine (47.5 g, 65.5 ml) and 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one (30 g) at 23-30°C. The content was heated to 63-65°C and maintained till completion of reaction. After completion of reaction, the reaction mass was cooled, filtered and dried to give title compound.
  • Paliperidone (37.5 g) was suspended into dichloromethane (562.5ml) and methanol (900 ml) at 23-30°C. The content was heated to 48-50°C to obtain a clear solution. Clear solutions were treated with carbon, dichloromethane/methanol mixture was distilled at 40-66°C under normal pressure up to 550 ml solution remain in the reaction mass. Thereafter the mass was cooled, filtered and dried to obtain title compound.
  • Paliperidone (37.5 g) was suspended into dichloromethane (562.5ml), triethylamine (12.3ml) and methanol (900 ml) at 23-30°C. The content was heated to 48-50°C to obtain a clear solution. Clear solutions were treats with carbon, dichloromethane/methanol mixture was distilled at 40-66°C under normal pressure Up to 550 ml solution remain in the reaction mass. Thereafter the mass was cooled, filtered and dried to obtain title compound.
  • Paliperidone (37.5 g) was suspended into acetone (37.5ml) and Methanol (375 ml) at 23-30°C. The content was heated to 60-65°C and stirred at 60-65°C for 1-2 hrs and thereafter the reaction mass was cooled to 20-25°C, filtered and dried to obtain title compound.

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

Abstract

L'invention concerne un procédé amélioré de préparation de palipéridone pure, représentée par la formule I.
PCT/IB2011/002312 2010-09-30 2011-09-29 Procédé de préparation de palipéridone Ceased WO2012042368A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2900/CHE/2010 2010-09-30
IN2900CH2010 2010-09-30

Publications (1)

Publication Number Publication Date
WO2012042368A1 true WO2012042368A1 (fr) 2012-04-05

Family

ID=44906242

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/002312 Ceased WO2012042368A1 (fr) 2010-09-30 2011-09-29 Procédé de préparation de palipéridone

Country Status (1)

Country Link
WO (1) WO2012042368A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN107311998A (zh) * 2017-06-28 2017-11-03 济南康和医药科技有限公司 一种高纯度帕利哌酮中间体的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2008021346A2 (fr) 2006-08-14 2008-02-21 Teva Pharmaceutical Industries Ltd. Palipéridone pure et ses procédés d'obtention
US20080214809A1 (en) 2006-08-23 2008-09-04 Ben-Zion Dolitzky Process for the synthesis of CMHTP and intermediates thereof
WO2009010988A1 (fr) * 2007-07-19 2009-01-22 Natco Pharma Limited Procédé amélioré, industriellement viable pour la préparation de palipéridone de haute pureté
WO2009144288A1 (fr) * 2008-05-29 2009-12-03 Inke, S.A. Procédé de fabrication de la palipéridone et d’intermédiaires pour celui-ci
WO2010064134A2 (fr) * 2008-12-05 2010-06-10 Cadila Pharmaceuticals Ltd. Procédé de synthèse de la palipéridone

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2008021346A2 (fr) 2006-08-14 2008-02-21 Teva Pharmaceutical Industries Ltd. Palipéridone pure et ses procédés d'obtention
US20080214809A1 (en) 2006-08-23 2008-09-04 Ben-Zion Dolitzky Process for the synthesis of CMHTP and intermediates thereof
WO2009010988A1 (fr) * 2007-07-19 2009-01-22 Natco Pharma Limited Procédé amélioré, industriellement viable pour la préparation de palipéridone de haute pureté
WO2009144288A1 (fr) * 2008-05-29 2009-12-03 Inke, S.A. Procédé de fabrication de la palipéridone et d’intermédiaires pour celui-ci
WO2010064134A2 (fr) * 2008-12-05 2010-06-10 Cadila Pharmaceuticals Ltd. Procédé de synthèse de la palipéridone

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN107311998A (zh) * 2017-06-28 2017-11-03 济南康和医药科技有限公司 一种高纯度帕利哌酮中间体的制备方法
CN107311998B (zh) * 2017-06-28 2019-05-14 济南康和医药科技有限公司 一种高纯度帕利哌酮中间体的制备方法

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