WO2010089643A1 - Procédé amélioré de préparation de la palipéridone - Google Patents

Procédé amélioré de préparation de la palipéridone Download PDF

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Publication number
WO2010089643A1
WO2010089643A1 PCT/IB2010/000178 IB2010000178W WO2010089643A1 WO 2010089643 A1 WO2010089643 A1 WO 2010089643A1 IB 2010000178 W IB2010000178 W IB 2010000178W WO 2010089643 A1 WO2010089643 A1 WO 2010089643A1
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WO
WIPO (PCT)
Prior art keywords
paliperidone
water
alcohol
stirred
organic base
Prior art date
Application number
PCT/IB2010/000178
Other languages
English (en)
Inventor
Keval Rameshchandra Sodagar
Vineet Malik
Sudhir Hukamchand Jain
Sanjay Natvarlal Parikh
Arun Omprakash Sharma
Uday Rajaram Bapat
Indravadan Ambalal Modi
Original Assignee
Cadila Pharmaceuticals 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 Cadila Pharmaceuticals Ltd. filed Critical Cadila Pharmaceuticals Ltd.
Publication of WO2010089643A1 publication Critical patent/WO2010089643A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

  • TITLE AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE
  • the invention relates to an improved process for the preparation of paliperidone in high yield and purity.
  • the purity of paliperidone obtained by the present invention is ⁇ 99.7 % by HPLC 1 wherein total impurity is less than about 0.3 % and each individual impurity is less than about 0.1 %.
  • Paliperidone is known as 9-hydroxy risperidone and useful for the treatment of schizophrenia.
  • 9-hydroxy risperidone is a metabolite of risperidon.
  • US Patent No. 4,804,663 and 5,158,952 describes a variety of 3-piperidinyM ,2- benzisoxazole derivatives and their processes along with their pharmaceutical compositions and methods of use. Paliperidone was first disclosed in US patent No. 5,158,952, and 5,254,556 (herein after designated as US '952 & US '556 patents respectively).
  • WO2008/021346 describes the purification of paliperidone wherein paliperidone is crystallized by combining a solution of paliperidone in a first solvent followed by addition of an anti solvent and discloses the use of C 1 ⁇ alcohol as solvent followed by water as anti-solvent wherein water is used in large quantity.
  • the first solvent is selected from group consisting of dichloromethane, dioxane, and C 1 to C 4 alkyl alcohols.
  • the anti-solvent is selected from group consisting of C 3 to C 6 ketones, C 3 to C 6 ethers, aceton ' rtrile, C 3 to C 7 straight and cyclic carbohydrates and water.
  • PCT applications WO 2008/021345 describes a process for preparing paliperidone comprising reacting 3-(2-chloroethyl)-6,7,8.9-tetrahydro-9-hydroxy-2-methyl-4H-pymdo-[1 ,2- a]- pyrimidin-4-one or salt thereof and 6-fluoro-3-piperidino-1,2-benzisoxazole or salt thereof in the presence of an inorganic base.
  • the object of present invention is to provide simple, reproducible, cost-effective, industrially scalable process for the preparation of paliperidone giving purity over 99.5%.
  • Another object of the invention is to provide an alternative process for the preparation of paliperidone by reacting 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9- tetrahydro-4W-pyrido-[1,2-a]-pyrimidin-4-one or its acid addition salt with 6-fluoro-3- p ⁇ peridin-4-yl-1 ,2-benzisoxazole or its acid addition salt in presence of an organic base.
  • Yet another object of the invention is to provide an improved process for purification of paliperidone having each individual impurity ⁇ 0.1 %.
  • Yet another object of the invention is to provide an improved process for purification of paliperidone having total impurity ⁇ 0.3 %.
  • Yet another object of the invention is to provide alcohol-water mixture as an alternate solvent for purification of paliperidone. Yet another object of the invention is to provide alcohol-water mixture as co-solvent for purification of paliperidone wherein co-solvent ration is ranging from 90:10 to 85:15 respectively.
  • Yet another object of the invention is to minimize the level of impurities like 3-[2-[4-(6- fluoro-1 , 2-benzisoxazol-3-yl)-1 -oxido-piperidin-1 -yl]- €thyl]-9-hydroxy-2-methyl-6, 7,8, 9- tetrahydro-4H-pyrido-[1 ,2-a]-pyrimid ⁇ n-4-one (N-oxide paliperidone) in desired final product.
  • the present invention provides an improved process for the preparation of paliperidone in high yield and purity over 99% by HPLC comprising reaction of 3-(2- chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1 ,2-a]-pyrimidi ⁇ -4-one or its acid addition salt with 6-fluoro-3-p ⁇ peridin-4-y
  • paliperidone is prepared comprising of following steps: a.
  • the N-alkylation process as described above uses an organic solvent which is preferably selected from Ci -6 alcohol, more preferably methanol.
  • the process is also carried out in presence of an organic base which is preferably nitrogen containing organic base selected from tertiary amines such as (Ri)(R 2 )(R 3 )N wherein Ri 1 R 2 , R 3 is preferably Ci. ⁇ alkyl; N-C 1-4 alkyl, morpholi ⁇ e; N- C 1 ⁇ alkyl pyrrolidene; N-C 1-4 alkyl piperidine; N-C 1 ⁇ alkyl aniline; preferably selected from trilakylamines such as diisopropyl ethyl amine.
  • the halide of halogen exchange catalysis ion is Br or I, preferably iodide.
  • the halogen exchange catalysis reagent is selected from sodium iodide, potassium iodide, cesium iodide, calcium iodide, ammonium iodide preferably potassium iodide.
  • the reaction is carried at 25 0 C to 150 0 C, preferably at 50 0 C to 125 0 C more preferably at 60°C-65°C.
  • the process involves use of water and / or an organic solvent for the washing of solid material wherein the suitable organic solvent is selected from ethyl acetate, 2-propanol, acetonitrile, alcohol, preferably methanol.
  • the purification of crude paliperidone is carried out using variety of organic solvent.
  • the acetonitrile, DMF, Ethyl acetate, water, acetone, n-pentanol, hexane and mixtures were used for the purification of crude paliperidone.
  • Alcohol water mixture is preferred for the purification of paliperidone.
  • the crude paliperidone is purified with alcohol and water mixture wherein alcohol is preferred from C M O alcohol preferably moderately water soluble alcohols.
  • the more preferable alcohol water mixture is C « alcohol and water mixture.
  • the preferred mode of present invention is performed the purification using pentanol water mixture.
  • the present invention provides a particular ratio of n-pentanol and water mixture wherein alcohol becomes miscible at high temperature and provides homogeneous solvent system wherein water acts as a co-solvent.
  • the crystallization of paliperidone is carried out using the co- solvent system.
  • the n-pentanol-water composition ranges from about 85 to 95 n-pentanol with water in 15 to 5 ratio.
  • the preferable composition is n-pentanol : water is 90 : 10.
  • the purification is optionally repeated upon requirement.
  • the paliperidone obtained by above process is having HPLC purity about ⁇ 99.7% or more and chemical purity over 99.9%.
  • the total impurity in end product is ⁇ 0.3 % and every impurity is ⁇ 0.1%.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation de la palipéridone avec une pureté et un rendement élevés. La pureté de la palipéridone est d'environ 99,7 % par HPLC, les impuretés totales représentant moins d'environ 0,3 % et chaque impureté individuelle représentant moins d'environ 0,1 %. L'invention concerne également la fourniture du co-solvant alcool-eau pour la purification de la palipéridone.
PCT/IB2010/000178 2009-02-03 2010-02-01 Procédé amélioré de préparation de la palipéridone WO2010089643A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN212/MUM/2009 2009-02-03
IN212MU2009 2009-02-03

Publications (1)

Publication Number Publication Date
WO2010089643A1 true WO2010089643A1 (fr) 2010-08-12

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ID=42541706

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/000178 WO2010089643A1 (fr) 2009-02-03 2010-02-01 Procédé amélioré de préparation de la palipéridone

Country Status (1)

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WO (1) WO2010089643A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035554A1 (fr) * 2010-09-14 2012-03-22 Megafine Pharma (P) Ltd. Procédé amélioré de préparation de palipéridone très pure
CN106866665A (zh) * 2017-04-01 2017-06-20 上海华源医药科技发展有限公司 一种帕利哌酮的制备方法

Citations (3)

* 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
US20070293671A1 (en) * 2004-07-08 2007-12-20 Laszlo Czibula Process for the Preparation of Risperidone
WO2008021345A2 (fr) * 2006-08-14 2008-02-21 Teva Pharmaceutical Industries Ltd. Procédé de synthèse de la 9-hydroxy-rispéridone (palipéridone)

Patent Citations (3)

* 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
US20070293671A1 (en) * 2004-07-08 2007-12-20 Laszlo Czibula Process for the Preparation of Risperidone
WO2008021345A2 (fr) * 2006-08-14 2008-02-21 Teva Pharmaceutical Industries Ltd. Procédé de synthèse de la 9-hydroxy-rispéridone (palipéridone)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035554A1 (fr) * 2010-09-14 2012-03-22 Megafine Pharma (P) Ltd. Procédé amélioré de préparation de palipéridone très pure
CN106866665A (zh) * 2017-04-01 2017-06-20 上海华源医药科技发展有限公司 一种帕利哌酮的制备方法

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