WO2004016589A2 - Procede de production de donepezil hydrochlorure tres pur - Google Patents

Procede de production de donepezil hydrochlorure tres pur Download PDF

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Publication number
WO2004016589A2
WO2004016589A2 PCT/IL2003/000665 IL0300665W WO2004016589A2 WO 2004016589 A2 WO2004016589 A2 WO 2004016589A2 IL 0300665 W IL0300665 W IL 0300665W WO 2004016589 A2 WO2004016589 A2 WO 2004016589A2
Authority
WO
WIPO (PCT)
Prior art keywords
donepezil
purity
hydrochloride
donepezil hydrochloride
acid
Prior art date
Application number
PCT/IL2003/000665
Other languages
English (en)
Other versions
WO2004016589A3 (fr
Inventor
Boris Tishin
Alexander Vilensky
Pavel Potyabin
Original Assignee
Finetech Laboratories Ltd.
Gutman, Arie, L.
Nisnevich, Gennady
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 Finetech Laboratories Ltd., Gutman, Arie, L., Nisnevich, Gennady filed Critical Finetech Laboratories Ltd.
Priority to AU2003249565A priority Critical patent/AU2003249565A1/en
Publication of WO2004016589A2 publication Critical patent/WO2004016589A2/fr
Publication of WO2004016589A3 publication Critical patent/WO2004016589A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • the present invention relates to a process for the preparation of highly pure Donepezil hydrochloride.
  • ARICEPT Applicant: Eisai Medical Research
  • tablettes useful as a therapeutic and ameliorating agent (tablets) for Alzheimer-type senile dementia, particularly as a prophylactic.
  • Donepezil hydrochloride is produced by first producing Donepezil, which is a free base, and then converting it into a hydrochloride.
  • Donepezil base is used as a precursor for the production of Donepezil hydrochloride.
  • Donepezil hydrochloride was prepared from the resulting purified Donepezil base by treating the base with HCl/EtOAc and re-crystallizing the resulting solid from MeOH/i-Pr 2 0 (H. Sugimoto et al., J. Med. Chem., 1995, v. 38, 481 and Eisai Co., U.S. 5,100,901).
  • Donepezil hydrochloride An additional process for production of Donepezil hydrochloride involves reacting a Donepezil intermediate with halogenated benzyl to obtain a Donepezil quaternary ammonium salt, hydrogenation of the quaternary ammonium salt to produce Donepezil base, followed by addition of HCl to produce Donepezil hydrochloride (US 6,252,081).
  • the present invention provides according to a first aspect thereof, a process for preparing highly pure Donepezil hydrochloride represented by the following formula
  • the obtained salt has a liquid chromatography (LC) purity (relative area method) of higher than 97% and a content of each individual impurity not exceeding 0.02 % (by area), which process comprises: intramolecular cyclization of 2-(3,4-dimethoxybenzyl)-3-(N-benzyl- 4-piperidine)propionic acid [II]
  • Donepezil base treating the donepezil base with HCl without isolating Donepezil base to form Donepezil hydrochloride; and optionally crystallizing the Donepezil hydrochloride to give the salt of desired LC purity.
  • Donepezil hydrochloride prepared by the method of the present invention has a liquid chromatography (LC) purity (relative area method) of at least 99.9%.
  • LC liquid chromatography
  • the present invention provides a scalable industrial process for the preparation of pure Donepezil hydrochloride having a liquid chromatography purity (relative area method) of higher than 97 %, preferably higher than 98%, more preferably higher than 99% and even more preferably higher than 99.9%, and with a content of each individual impurity not exceeding 0.02 % (by area), which process comprises forming Donepezil base in solution and treating the Donepezil base solution with HCl without prior isolation of Donepezil base; and optionally re-crystallizing the hydrochloride salt to give Donepezil hydrochloride of desired liquid chromatography purity.
  • a liquid chromatography purity relative area method
  • Donepezil base in solution may be obtained by intramolecular cyclization of 2-(3,4-dimethoxybenzyl)-3-(N-benzyl- 4-piperidine)propionic acid [II] or a salt thereof, as described above or by any other process which affords highly pure Donepezil base as end product, without prior isolation and purification.
  • the described invention provides a process for the preparation of highly pure Donepezil hydrochloride by cyclization of a compound of formula [II] or a salt thereof.
  • the cyclization of compound [II] is carried out under
  • the cyclization in the process of the present invention is carried out in the presence of protic acids or Lewis acids or a mixture of protic and Lewis acids.
  • protic acids are trifluoromethanesulfonic acid, methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonic acid, sulfuric acid, hydrogen fluoride and hydrogen chloride.
  • Lewis acids are zinc chloride, zinc bromide, aluminum chloride, aluminum bromide, titanium chloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride and sulfuryl chloride.
  • the cyclization may be carried out in the presence of a solvent.
  • the solvent is a halogenated solvent.
  • halogenated solvents are dichloromethane, chloroform, dichloroethane, tetrachloroethane, chlorobenzene, dichlorobenzene and mixtures thereof.
  • the solvent is nitromethane, nitroethane, nitrobenzene, ether and mixtures thereof.
  • the compound [II] or its salt has liquid chromatography purity (relative area method) of at least 97 %. More preferably, the compound [II] or its salt has liquid chromatography purity (relative area method) of at least 98 %. Most preferably, the compound [II] or its salt has liquid chromatography purity (relative area method) of at least 99 %.
  • liquid chromatography purity relative area method
  • liquid cliromatography (LC) purity was determined by separating a sample by high performance liquid chromatography (HPLC) under the following conditions, and calculating the area percentage thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de Donepezil hydrochlorure possédant une pureté obtenue par chromatographie liquide (méthode de mesure de surface relative) de plus de 97 %, la teneur en impuretés individuelles ne dépassant 0,02 % par superficie. Ledit procédé consiste à former une base Donepezil dans une solution et à traiter la solution à base Donezepil avec un HCl, sans isolement préalable de la base Donezepil ; et éventuellement à recristalliser l'hydrochlorure pour donner au Donezepil hydrochlorure la pureté voulue obtenue par chromatographie liquide. La base Donezepil en solution peut être obtenue par cyclisation intramoléculaire d'acide 2-(3,4-diméthoxybenzyl)-3-(N-benzyl-4-pipéridine)propionique ou d'un sel de celui-ci.
PCT/IL2003/000665 2002-08-14 2003-08-11 Procede de production de donepezil hydrochlorure tres pur WO2004016589A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003249565A AU2003249565A1 (en) 2002-08-14 2003-08-11 Process for production of highly pure donepezil hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL151253 2002-08-14
IL15125302A IL151253A0 (en) 2002-08-14 2002-08-14 Process for production of highly pure donepezil hydrochloride

Publications (2)

Publication Number Publication Date
WO2004016589A2 true WO2004016589A2 (fr) 2004-02-26
WO2004016589A3 WO2004016589A3 (fr) 2004-06-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2003/000665 WO2004016589A2 (fr) 2002-08-14 2003-08-11 Procede de production de donepezil hydrochlorure tres pur

Country Status (3)

Country Link
AU (1) AU2003249565A1 (fr)
IL (1) IL151253A0 (fr)
WO (1) WO2004016589A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007135408A1 (fr) * 2006-05-18 2007-11-29 Pliva Hrvatska D.O.O. Impuretés du donépézil
WO2008126995A1 (fr) * 2007-04-12 2008-10-23 Dong Wha Pharm. Ind. Co., Ltd. Procédé de préparation d'un intermédiaire de donépézil
US7592459B2 (en) 2004-09-29 2009-09-22 Chemagis Ltd. Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride
KR100953038B1 (ko) * 2007-12-12 2010-04-14 일동제약주식회사 염산 도네페질의 개량된 제조방법
WO2011051957A2 (fr) * 2009-10-30 2011-05-05 Neuland Laboratories Ltd. Procédé de préparation d'hydrochlorure de donépézil

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022584A1 (fr) * 1995-12-15 1997-06-26 Pfizer Inc. Procedes de preparation de 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine et intermediaires utilises a cet effet
WO2000009483A2 (fr) * 1998-08-17 2000-02-24 Finetech Ltd. Nouveau procede et intermediaires pour la production de donepezil et de ses composes apparentes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022584A1 (fr) * 1995-12-15 1997-06-26 Pfizer Inc. Procedes de preparation de 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine et intermediaires utilises a cet effet
WO2000009483A2 (fr) * 1998-08-17 2000-02-24 Finetech Ltd. Nouveau procede et intermediaires pour la production de donepezil et de ses composes apparentes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7592459B2 (en) 2004-09-29 2009-09-22 Chemagis Ltd. Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride
WO2007135408A1 (fr) * 2006-05-18 2007-11-29 Pliva Hrvatska D.O.O. Impuretés du donépézil
WO2008126995A1 (fr) * 2007-04-12 2008-10-23 Dong Wha Pharm. Ind. Co., Ltd. Procédé de préparation d'un intermédiaire de donépézil
KR100953038B1 (ko) * 2007-12-12 2010-04-14 일동제약주식회사 염산 도네페질의 개량된 제조방법
WO2011051957A2 (fr) * 2009-10-30 2011-05-05 Neuland Laboratories Ltd. Procédé de préparation d'hydrochlorure de donépézil
WO2011051957A3 (fr) * 2009-10-30 2012-10-04 Neuland Laboratories Ltd. Procédé de préparation d'hydrochlorure de donépézil

Also Published As

Publication number Publication date
AU2003249565A1 (en) 2004-03-03
IL151253A0 (en) 2003-04-10
AU2003249565A8 (en) 2004-03-03
WO2004016589A3 (fr) 2004-06-10

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