WO2005076749A2 - Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine - Google Patents

Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine Download PDF

Info

Publication number
WO2005076749A2
WO2005076749A2 PCT/IN2005/000044 IN2005000044W WO2005076749A2 WO 2005076749 A2 WO2005076749 A2 WO 2005076749A2 IN 2005000044 W IN2005000044 W IN 2005000044W WO 2005076749 A2 WO2005076749 A2 WO 2005076749A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
benzyl
methyl
dimethoxy
indanon
Prior art date
Application number
PCT/IN2005/000044
Other languages
English (en)
Other versions
WO2005076749A3 (fr
Inventor
Shailendra Kumar Dubey
Bhausaheb Chavhan
Amit Kumar Sharma
Soumendu Paul
Rajesh Kumar Thaper
Sushil Kumar Dubey
Jag Mohan Khanna
Original Assignee
Jubilant Organosys Limited
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 Jubilant Organosys Limited filed Critical Jubilant Organosys Limited
Publication of WO2005076749A2 publication Critical patent/WO2005076749A2/fr
Publication of WO2005076749A3 publication Critical patent/WO2005076749A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • 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
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention in general, relates to the field of chemical synthesis of cholinesterase inhibitor and more particularly, but without restriction to the preferred embodiments hereinafter described in accordance with the best mode of practice, the present invention provides a process for producing pure l-benzyl-4-[(5,6-dimethoxy-l- indanon-2-yl)methyl]piperidine (donepezil) or its salt thereof employing novel starting compound.
  • Donepezil of formula 1, is a cholinesterase inhibitor used in the treatment of mild to moderate cases of SDAT (Senile Dementia of Alzheimers Type). Donepezil's unique chemical structure makes it more specific for effects on the Alzheimer disease than other drugs.
  • US Patent No. 5,606,064 describes another route to prepare donepezil via the reduction of l-benzyl-4-[(5,6-dimethoxy-l-indanon-2-ylidene)methyl]pyridinium salt in presence of platinum dioxide as catalyst and methanol as solvent with a yield of 58.5% (Scheme 2).
  • Scheme 2 the reduction of an olefinic bond and a pyridinium ring in presence of a benzyl group, as described in the process is difficult to achieve and leads to unwanted side products mainly debenzylated product and the reaction time for completion is also too long which is 24 hrs.
  • US Patent No. 6,252,081 discloses a process, which involves the selective reduction of pyridinium ring of l-benzyl-4-[(5,6-dimethoxy-l-indanon-2-yl)methyl]pyridinium salt using platinum oxide as catalyst. This process also leads to the formation of impurities, which are difficult to separate and affects the overall reaction yield along with the purity of the compound (Scheme 3).
  • US Patent Application No. 20040143121 discloses the process for the preparation of donepezil which involves the reduction of compound 4-[(5,6-dimethoxy-l-indanon-2- ylidene)methyl]pyridine using platinum dioxide or Pd/C as catalyst, in a mixture of solvents
  • WO2004082685 describes the preparation of donepezil which comprises the two step reduction starting from 4-[(5,6-dimethoxy-l-indanon-2- ylidene)methyl]pyridine via the preparation of intermediate 4-[(5,6-dimethoxy-l- indanon-2-yl)methyl]pyridine using mixture of methanol and methylene chloride as a solvent system.
  • WO2003082820 discloses preparation of 1, 2,3, 6-tetrahydropyri dine- 1-indanone derivatives (Scheme 5).
  • the present invention seeks to overcome all such past limitations and provides a novel process for producing donepezil.
  • a novel process for producing l-benzyl-4-[(5,6-dimethoxy-l-indanon-2- yl)methyl]piperidine of formula [I] or salt thereof wherein the process comprises employing a novel starting compound i.e. 1,2,3, 6-tetrahydropyridine derivative of formula [V].
  • a novel process for producing l-benzyl-4-[(5,6-dimethoxy-l-indanon- 2yl)methyl]piperidine of formula [I] or salt thereof employing an intermediate 1- benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]-l,2,3,6-tetrahydropyridine of formula [II] or salt thereof, wherein the process comprising reducing l-benzyl-4-[(5,6- dime-hoxy-l-indanon-2yl)methylj-l,2.3,6-tetrabydropyridine using reducing agent in presence of solvent and optionally in presence of phase transfer catalyst to produce pure l-benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]piperidine of formula [I] or salt thereof.
  • the disclosed embodiment of the present invention deals with a novel and industrially amenable process for producing highly pure donepezil i.e. l-benzyl-4-[(5,6-dimethoxy- l-indanon-2-yl)methyl]piperidine of formula [I] or salt thereof.
  • Scheme 6 represents the reaction scheme of the present invention, wherein Q is a good leaving group, which can be selected from chloride, bromide, iodide, mesylate or tosylate; and R is represented by CH 2 Ph.
  • indanone derivative of formula [IV] is treated with a novel tetrahydropyridme derivative of formula [V] in the presence of a base at a suitable temperature and in an appropriate solvent to obtain an intermediate of formula [II] with an impurity of formula [X].
  • concentration of impurity formed is varied depending upon the choice of the base used and the reaction conditions. The reaction conditions are dependent on the choice of the base and solvent system used.
  • Base used herein in step (a) of the reaction process is selected from the group consisting of, but not limited to, potassium carbonate, potassium tert-butoxide, sodium methoxide, sodium hydride, n-butyl lithium or lithium diisopropylamide (LDA).
  • Solvent used herein in step (b) of the reaction process is selected from the group comprising tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), dimethylformamide, toluene, or cyclohexane alone or a mixture thereof.
  • MIBK methyl isobutyl ketone
  • MEK methyl ethyl ketone
  • dimethylformamide toluene
  • toluene or cyclohexane alone or a mixture thereof.
  • phase transfer catalyst is also option all ⁇ ' ' used in the process step, where indanone derivative of formula [IV] is treated with a novel tetrahydropyridme derivative of formula [V] in the presence of a base at a suitable temperature and in an appropriate solvent to obtain an intermediate of formula [II].
  • phase transfer catalyst increases the reaction rate upto almost three-fold.
  • the phase transfer catalyst used herein is selected from the group consisting of, but not limited to, ammonium based phase transfer reagent, - phosphonium based phase transfer reagent, crown ethers - for example tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, benzyl txiethylarmrionium chloride, benzyl tributylammonium chloride, tetramethylammonium chloride, tetarbutylphosphonium chloride, dibenzo-18- crown-6.
  • the reduction of l-benzyl-4-[(5.6-dimethoxy-l-indanon-2yl)methyl]-l-2,3,6- tetrahydro pyridine, an intermediate of formula [II] to form a final product donepezil, i.e. l-benzyl-4-[(5,6-dimethoxy-l-indanon-2-yl)methyllpiperidine of formula [I], may be achieved by hydrogenation in the presence of catalyst.
  • the catalyst used for the reduction are the customary hydrogenation catalysts known in the organic chemistry, for example, but not limited to, noble metals or their derivatives such as platinum, palladium, rhodium, ruthenium and the like.
  • the reaction described herein is carried out in solvent or a mixture thereof.
  • the solvent used herein is selected from the group consisting of, but not limited to, lower alcohols such as methanol, ethanol, propanol, isopropanol and butanol, chlorinated hydrocarbons such as methylene chloride, esters such as ethyl acetate and isopropyl acetate, polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or a mixture thereof.
  • the hydrogenation may be carried out at normal pressure or at elevated pressure depending on the choice of catalyst. It may be carried out at a hydrogen pressure in the range of 35 psi to 100 psi. In particular, it may be carried out at a hydrogen pressure in the range of 60-80 psi.
  • the hydrogenation may be carried out at a temperature from about 40°C to 70°C, more preferably 50 to 60°C.
  • the aforementioned compound of formula [V] is prepared by the reduction of the pyridine-4-carboxaldehyde [IX] using reducing agent in presence of solvent to get a compound of formula [VIII].
  • the reducing agent used herein is selected from the group consisting of, but not limited to, metal hydrides such as lithium aluminum hydride, sodium borohydride or boranes such as ⁇ diborane, more preferably " sodium borohydride.
  • the solvent used herein is selected from the group consisting of lower alcohol such as methanol, ethanol, isopropanol or butanol, more preferably methanol.
  • the produced compound of formula [N ⁇ i] disclosed herein may be prepared by another way also.
  • the compound of formula [VIII] is then treated with benzylating agent in a solvent to get N-benzylated-4-hydroxymethylpyridinium halide of formula [VII].
  • the benzylating agent used is selected from the group consisting of, but not limited to, benzyl bromide, benzyl chloride, benzyl iodide, benzyl mesylate or benzyl tosylate, more preferably benzyl bromide.
  • the solvent used is selected from the group consisting of but not limited to ethers such as dioxane and tetrahydrofuran; chlorinated hydrocarbons such as methylene chloride; ketones such as acetone and methyl isobutyl ketone (MLBK); acetonitrile or mixture thereof.
  • N-benzyl-4-hydroxymethylpyridinium bromide [VII] is selectively reduced using reducing agent such as sodium borohydride in a solvent such as lower alcohol for example methanol, ethanol, propanol, isopropanol or butanol more preferably methanol to give N-benzyl-4-hydroxymethyl- 1,2,3, 6-tetrahydropyridine [VI].
  • reducing agent such as sodium borohydride
  • a solvent such as lower alcohol for example methanol, ethanol, propanol, isopropanol or butanol more preferably methanol
  • the hydroxyl group of compound [VI] is then converted into a good leaving group Q to produce a novel compound 1,2,3,6- tetrahydropyridine derivative of formula [V].
  • the good leaving group is selected from the group consisting of, but not limited to, halogenating agent such as phosphoryl chloride, thionyl chloride, phosphorus trihalide, phosphorus pentahalide and tosyl chloride or mesyl chloride, more preferably thionyl chloride in a solvent such as dichloromethane

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un nouveau procédé de production d'une 1-benzyl-4-(5,6-diméthoxy-1-indanon-2-yl)méthyl]pipéridine (donépézil) représentée par la formule [I] par traitement d'un nouveau composé de départ dérivé d'une 1,2,3,6-tétrahydropyridine représenté par la formule [V] avec un 5,6-diméthoxy-1-indanone représenté par la formule [IV] pour obtenir une 1-benzyl-4-[(5,6-diméthoxy-1-indanon-2yl)méthyl]-1,2,3,6-tétrahydro pyridine intermédiaire représentée par la formule [II], et par réduction de celle-ci afin d'obtenir la 1-benzyl-4-[(5,6-diméthoxy-1-indanon-2-yl)méthyl]pipéridine représentée par la formule [I]. L'invention concerne également le procédé de préparation du nouveau composé représenté par la formule [V].
PCT/IN2005/000044 2004-02-11 2005-02-11 Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine WO2005076749A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN193DE2004 2004-02-11
IN193/DEL/2004 2004-02-11

Publications (2)

Publication Number Publication Date
WO2005076749A2 true WO2005076749A2 (fr) 2005-08-25
WO2005076749A3 WO2005076749A3 (fr) 2006-06-08

Family

ID=34856868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000044 WO2005076749A2 (fr) 2004-02-11 2005-02-11 Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine

Country Status (1)

Country Link
WO (1) WO2005076749A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007077443A1 (fr) * 2006-01-04 2007-07-12 Cipla Limited Procede et intermediaire pour la preparation de donepezil
WO2008126995A1 (fr) * 2007-04-12 2008-10-23 Dong Wha Pharm. Ind. Co., Ltd. Procédé de préparation d'un intermédiaire de donépézil
US8247563B2 (en) 2006-12-11 2012-08-21 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors
WO2014005421A1 (fr) 2012-07-03 2014-01-09 浙江海正药业股份有限公司 Dérivé de benzodioxole et son procédé de préparation et son utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6252081B1 (en) * 1998-01-16 2001-06-26 Eisai Co., Ltd. Process for production of donepezil derivative
WO2002002526A1 (fr) * 2000-07-03 2002-01-10 Eisai Co., Ltd. Compositions pharmaceutiques servant a stabiliser la tension intraoculaire
US20050124642A1 (en) * 2002-03-29 2005-06-09 Eisai Co., Ltd. (1-Indanone)-(1,2,3,6-tetrahydropyridine) compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6252081B1 (en) * 1998-01-16 2001-06-26 Eisai Co., Ltd. Process for production of donepezil derivative
WO2002002526A1 (fr) * 2000-07-03 2002-01-10 Eisai Co., Ltd. Compositions pharmaceutiques servant a stabiliser la tension intraoculaire
US20050124642A1 (en) * 2002-03-29 2005-06-09 Eisai Co., Ltd. (1-Indanone)-(1,2,3,6-tetrahydropyridine) compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CLARK J K.: 'Quatemary Salts of E2020 Analogues as Acetylcholinesterase Inhibitors for the Reversal of Neuromuscular Block.' BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. vol. 12, June 2002, pages 2565 - 2568, XP002289468 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007077443A1 (fr) * 2006-01-04 2007-07-12 Cipla Limited Procede et intermediaire pour la preparation de donepezil
JP2009524599A (ja) * 2006-01-04 2009-07-02 シプラ・リミテッド ドネペジルを調製するための方法および中間体
US8030491B2 (en) 2006-01-04 2011-10-04 Cipla Limited Process and intermediate for preparation of donepezil
US8247563B2 (en) 2006-12-11 2012-08-21 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors
US8580822B2 (en) 2006-12-11 2013-11-12 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors
WO2008126995A1 (fr) * 2007-04-12 2008-10-23 Dong Wha Pharm. Ind. Co., Ltd. Procédé de préparation d'un intermédiaire de donépézil
WO2014005421A1 (fr) 2012-07-03 2014-01-09 浙江海正药业股份有限公司 Dérivé de benzodioxole et son procédé de préparation et son utilisation
US9346818B2 (en) 2012-07-03 2016-05-24 Zhejiang Hisun Pharmaceutical Co., Ltd. Benzodioxole derivative and preparation method and use thereof

Also Published As

Publication number Publication date
WO2005076749A3 (fr) 2006-06-08

Similar Documents

Publication Publication Date Title
EA012911B1 (ru) Способ получения высокочистого полиморфа (i) донепезила гидрохлорида
EP1939178B1 (fr) Procédé de production de la 1-benzyl-4-[(5,6-diméthoxy-1indanon)-2-yl]méthylpipéridine ou de son chlorhydrate
EP2278970B1 (fr) Procédé de préparation de chlorhydrate de donépézil
US7795438B2 (en) Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride
US8318942B2 (en) Process for preparing Donepezil and its derivatives
WO2007108011A2 (fr) Procede de preparation de donepezile de grande purete
WO2005076749A2 (fr) Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine
US7148354B2 (en) Process for preparation of donepezil
US20060041140A1 (en) Preparation of intermediates for acetyl cholinesterase inhibitors
US6437136B2 (en) Process for the preparation of (−)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine
KR20080027885A (ko) １-벤질-４-[(５,６-디메톡시-１-인다논)-２-일리덴]메틸피페리딘의 제조 방법
US8124783B2 (en) Process for producing 1-benzyl-4-[5,6-dimethoxy-1-indanon-2-yl)methyl] piperidine or its salt thereof via novel intermediate
JP4427113B2 (ja) Ｎ−置換−ホルミルポリメチレンイミンの製造方法
JP2002537394A (ja) パロキセチンの製造方法
KR100953038B1 (ko) 염산 도네페질의 개량된 제조방법
KR100879120B1 (ko) 도네페질 및 그 중간체의 제조방법
CN117480174A (zh) 一种手性还原剂及合成手性尼古丁的方法
KR100947953B1 (ko) 신규 중간체를 통해1-벤질-4-[(5,6-디메톡시-1-인다논-2-일)메틸]피페리딘또는 이의 염을 제조하는 방법
JPS63192751A (ja) ４−ヒドロキシピペリジンの製造方法
US20020010155A1 (en) Novel process
EP0058072A2 (fr) Procédé et intermédiaires pour la préparation de pirbutérol et analogues

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase