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WO2009010987A1 - Procédé amélioré pour la préparation de chlorhydrate de palonosétron pur - Google Patents

Procédé amélioré pour la préparation de chlorhydrate de palonosétron pur Download PDF

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Publication number
WO2009010987A1
WO2009010987A1 PCT/IN2008/000313 IN2008000313W WO2009010987A1 WO 2009010987 A1 WO2009010987 A1 WO 2009010987A1 IN 2008000313 W IN2008000313 W IN 2008000313W WO 2009010987 A1 WO2009010987 A1 WO 2009010987A1
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WO
WIPO (PCT)
Prior art keywords
palonosetron hydrochloride
methanol
formula
aqueous
process according
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/IN2008/000313
Other languages
English (en)
Inventor
Janaki Rama Rao Ravi
Muddasani Pulla Reddy
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
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.)
Natco Pharma Ltd
Original Assignee
Natco 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 Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2009010987A1 publication Critical patent/WO2009010987A1/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
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • the present invention relates to an improved process for the preparation of pure Palonosetron Hydrochloride which is (3as)-2[(3s)-l-azabicyclo[2.2.2] Oct-3-yl]- 2,3,3a,4,5,6-hexahydro-lH-benz[de]isoquinoline-l-one monohydrochloride of formula-I.
  • I Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy treatment of cancer patients. It is marketed under the brand name 'Aloxi' and 'Onicit'.
  • Palonosetron Hydrochloride is introduced for the first time by SYNTEX INC., a U.S. based company.
  • Palonosetron Hydrochloride is a tricyclic 5-HT 3 receptor antagonist containing a bridged bicyclic amine substituent.
  • Serotonin a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and subsequently has been the subject of the substantial research. Serotonin also referred to as 5-hydroxytryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors.
  • 5-HT 5-hydroxytryptamine
  • 5-HT receptors are presently delineated into three major subclasifications-5HTi, 5-HT 2 and 5-HT 3 each of which may also be heterogenous. Receptors of the 5-HT 3 subclass pervade autonomic neurons and appear to regulate the release of a variety of neurotransmitters in the gastrointestinal, cardiovascular and central nervous systems.
  • 5-HT 3 receptors are located in high densities on neurons associated with the emetic reflex and drugs which block the interactions of serotonin at the 5-HT 3 receptor level, i.e., 5- HT 3 receptor antagonists posses potent anti-emetic properties. Such antagonists demonstrate utility for counteracting the emetic effects of cancer chemotherapy and radiotherapy.
  • the compound of formula-V as free base is hydrogenated in the presence of acetic acid, containing few drops of 70% perchloric acid, 20% palladium hydroxide-on-carbon at 85 0 C for 24 hours.
  • the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure.
  • the residue is dissolved in water, basified with ammonium hydroxide solution and extracted with ethyl acetate.
  • the solvent is evaporated to yield Palonosetron free base, which is recrystallized in ethanolic HCl, isopropyl alcohol, and ether to get Palonosetron HCl of formula-I.
  • the main objective of the present invention is to provide an improved process for catalytic hydrogenation of compound of formula-V, which is simple to adopt on commercial scale.
  • Another objective of the present invention is to provide an improved process for catalytic hydrogenation of compound of formula-V avoiding elevated temperatures.
  • Still another objective of the present invention is to provide an improved process for catalytic hydrogenation of compound of formula-V, which involves shorter reaction time.
  • Still another objective of the present invention is to produce palonosetron HCl of high purity (>99.8% by HPLC) suitable for pharmaceutical applications.
  • the present invention is related to an improved process for the preparation of palonosetron HCl of formula-I,
  • the solvent used as reaction medium in step (i) selected from lower aliphatic alcohols such as methanol, ethanol, isopropanol, n-butanol etc., preferably methanol.
  • the palladium catalyst used in step (ii) for hydrogenation is selected from 5% Pd/C, 10%
  • step (iii) 20% Palladium hydroxide on carbon etc., preferably 10% Pd/C.
  • Temperature of reaction mass in step (iii) is range of 25-75 0 C, more preferably 25-35°C.
  • the solvent used in step (v) for leaching the palonosetron hydrochloride salt is selected from aqueous lower aliphatic alcohols such as aqueous methanol, aqueous ethanol, aqueous isopropanol, preferably aqueous isopropanol.
  • the solvent used in step (vi) for the recrystallization of palonosetron hydrohloride salt is selected from lower aliphatic alcohols such as methanol, ethanol, isopropanol, n-butanol, etc.; esters such as ethyl acetate, methyl acetate; ketones such as acetone; ethers such as diethyl ether, isopropyl ether, tert-butylmethyl ether and hydrocarbons such as hexane, heptane, toluene, xylene or combination thereof.
  • lower aliphatic alcohols such as methanol, ethanol, isopropanol, n-butanol, etc.
  • esters such as ethyl acetate, methyl acetate
  • ketones such as acetone
  • ethers such as diethyl ether, isopropyl ether, tert-butylmethyl ether
  • hydrocarbons such as
  • Preferred alcoholic solvent is methanol and the ether solvent is tert-butyl methyl ether or a combination of methanol/tert-butyl methyl ether.
  • the temperature of reaction mass in step (vi) is 0-35 0 C preferably 10-35 0 C, more preferably 25-35 0 C.
  • isopropanol 180 ml is added, stirred for 20 min at room temperature and water (6.0 ml) is added. The resulting suspension is stirred at room temperature for 2 hours. The product is filtered of and dried for 2 hours at 65-70 0 C. The resulting white solid is dissolved in methanol (64 ml) at 60-65 0 C and charcoal (2.0 g) is added to the solution. The reaction mass is stirred at 60-65 0 C for 45 minutes and charcoal is filtered on hyflo bed and washed with methanol (10 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Otolaryngology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé amélioré et industriellement viable pour la préparation de chlorhydrate de palonosétron de haute pureté chimique (>99,8%) et chirale (> 99,8%), représenté par la formule I ((3as)-2[(3s)-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[dé]isoquinoline-1-one monochlorhydrate), obtenu à partir d'une réduction de 2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tétrahydro-1H-benz[dé]iso-quinolin-1-one chlorhydrate représenté par la formule VI. Dans l'état antérieur de la technique, un composé représenté par la formule VI ou sa base sont utilisés dans l'hydrogénation catalytique. Mais la sélection de solvants comme l'acide acétique ou le THF les rend commercialement non viables du fait du faible rendement et de la faible pureté du chlorhydrate de palonosétron. Dans le présent procédé, un solvant simple comme du méthanol et du palladium sur carbone facilement disponible sont utilisés pour augmenter le rendement et la pureté du chlorhydrate de palonosétron. Le chlorhydrate de palonosétron est utile en tant qu'agent anti-émétique utilisé au cours de la chimiothérapie pour le traitement de patients atteints du cancer et est commercialisé sous les marques 'Aloxi' et 'Onicit'.
PCT/IN2008/000313 2007-07-19 2008-05-16 Procédé amélioré pour la préparation de chlorhydrate de palonosétron pur Ceased WO2009010987A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1552/CHE/2007 2007-07-19
IN1552CH2007 2007-07-19

Publications (1)

Publication Number Publication Date
WO2009010987A1 true WO2009010987A1 (fr) 2009-01-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000313 Ceased WO2009010987A1 (fr) 2007-07-19 2008-05-16 Procédé amélioré pour la préparation de chlorhydrate de palonosétron pur

Country Status (1)

Country Link
WO (1) WO2009010987A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2231658A4 (fr) * 2007-12-13 2010-11-24 Glenmark Generics Ltd Base libre du palonosétron et son procédé de préparation
US20110213150A1 (en) * 2008-11-11 2011-09-01 Dr. Reddy's Laboratories Ltd. Preparation of crystalline palonosetron hydrochloride
US8123389B2 (en) 2010-02-12 2012-02-28 Lumenetix, Inc. LED lamp assembly with thermal management system
EP2448936A2 (fr) 2009-06-30 2012-05-09 Ranbaxy Laboratories Limited Procédés de préparation des formes i et ii de l'hydrochlorure de palonosétron
CN103012396A (zh) * 2012-12-27 2013-04-03 齐鲁制药有限公司 一种盐酸帕洛诺司琼异构体的转化方法
US8427036B2 (en) 2009-02-10 2013-04-23 Lumenetix, Inc. Thermal storage system using encapsulated phase change materials in LED lamps
US8632227B2 (en) 2008-03-02 2014-01-21 Lumenetix, Inc. Heat removal system and method for light emitting diode lighting apparatus
US9102857B2 (en) 2008-03-02 2015-08-11 Lumenetix, Inc. Methods of selecting one or more phase change materials to match a working temperature of a light-emitting diode to be cooled

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001824A1 (fr) * 1994-07-08 1996-01-25 F. Hoffmann-La Roche Ag Procede de preparation de 2-(1-azabicyclo[2.2.2.]oct-3-yl)-2,4,5,6-tetrahydro-1h-benz[de]isoquiloeine-1-one et de produit intermediaire
US20080058367A1 (en) * 2006-08-30 2008-03-06 Palle Raghavendracharyulu Venk Process for the purification of palonosetron or its salt
WO2008051539A2 (fr) * 2006-10-23 2008-05-02 Sicor Inc. Processus de préparation de sels de palonosetron
CN101186607A (zh) * 2006-11-15 2008-05-28 深圳海王药业有限公司 一种盐酸帕洛诺司琼的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001824A1 (fr) * 1994-07-08 1996-01-25 F. Hoffmann-La Roche Ag Procede de preparation de 2-(1-azabicyclo[2.2.2.]oct-3-yl)-2,4,5,6-tetrahydro-1h-benz[de]isoquiloeine-1-one et de produit intermediaire
US20080058367A1 (en) * 2006-08-30 2008-03-06 Palle Raghavendracharyulu Venk Process for the purification of palonosetron or its salt
WO2008051539A2 (fr) * 2006-10-23 2008-05-02 Sicor Inc. Processus de préparation de sels de palonosetron
CN101186607A (zh) * 2006-11-15 2008-05-28 深圳海王药业有限公司 一种盐酸帕洛诺司琼的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRUCE A KOWALCZYK ET AL: "Hydrogenation of a chiral 1H-Benz[de]isoquinolin-1-one and an Equilibration using Palladium catalyst", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, CAMBRIDGE, GB, vol. 1, 1 January 1997 (1997-01-01), pages 117 - 120, XP002482160 *
LU, QING-HUAI ET AL: "Synthesis of palonosetron", ZHONGGUO XINYAO ZAZHI , 16(13), 1027-1030 CODEN: ZXZHA6; ISSN: 1003-3734, 2007, XP008098650 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2231658A4 (fr) * 2007-12-13 2010-11-24 Glenmark Generics Ltd Base libre du palonosétron et son procédé de préparation
US8304544B2 (en) 2007-12-13 2012-11-06 Glenmark Generics Limited Palonosetron free base and process for its preparation
US8632227B2 (en) 2008-03-02 2014-01-21 Lumenetix, Inc. Heat removal system and method for light emitting diode lighting apparatus
US9102857B2 (en) 2008-03-02 2015-08-11 Lumenetix, Inc. Methods of selecting one or more phase change materials to match a working temperature of a light-emitting diode to be cooled
US20110213150A1 (en) * 2008-11-11 2011-09-01 Dr. Reddy's Laboratories Ltd. Preparation of crystalline palonosetron hydrochloride
EP2364312A4 (fr) * 2008-11-11 2012-05-02 Reddys Lab Ltd Dr Synthèse de chlorhydrate de palonosétron cristallin
US8427036B2 (en) 2009-02-10 2013-04-23 Lumenetix, Inc. Thermal storage system using encapsulated phase change materials in LED lamps
EP2448936A2 (fr) 2009-06-30 2012-05-09 Ranbaxy Laboratories Limited Procédés de préparation des formes i et ii de l'hydrochlorure de palonosétron
US8123389B2 (en) 2010-02-12 2012-02-28 Lumenetix, Inc. LED lamp assembly with thermal management system
US8783894B2 (en) 2010-02-12 2014-07-22 Lumenetix, Inc. LED lamp assembly with thermal management system
CN103012396A (zh) * 2012-12-27 2013-04-03 齐鲁制药有限公司 一种盐酸帕洛诺司琼异构体的转化方法

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