WO2006106531A1 - Processus de preparation d'escitalopram ou de ses sels d'addition acides - Google Patents

Processus de preparation d'escitalopram ou de ses sels d'addition acides Download PDF

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Publication number
WO2006106531A1
WO2006106531A1 PCT/IN2006/000124 IN2006000124W WO2006106531A1 WO 2006106531 A1 WO2006106531 A1 WO 2006106531A1 IN 2006000124 W IN2006000124 W IN 2006000124W WO 2006106531 A1 WO2006106531 A1 WO 2006106531A1
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WO
WIPO (PCT)
Prior art keywords
escitalopram
acid
mixture
base
solvent
Prior art date
Application number
PCT/IN2006/000124
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English (en)
Inventor
Santosh Laxman Goankar
Prasenjit Prafulla Das
Ambati Narahari Babu
Sulur G. Manjunatha
Original Assignee
Jubilant Organosys 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 Jubilant Organosys Ltd filed Critical Jubilant Organosys Ltd
Priority to EP06728421A priority Critical patent/EP1877394A1/fr
Publication of WO2006106531A1 publication Critical patent/WO2006106531A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans

Definitions

  • Escitalopram which is the S-enantiomer of well known antidepressant drug Citalopram, /. e. (S)- 1 -[3 -(dimethylamino)propyl] - 1 -(4-flouorphenyl)- 1 ,3 -dihydro-5 - isobenzofuran carbonitrile or a pharmaceutically acceptable salt thereof.
  • Citalopram is a well-known antidepressant drug that has now been in the market for some years and has the following structure shown in figure 1 :
  • Figure 1 It is a selective centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
  • Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication outlines a process for preparation of Citalopram from the corresponding 5-bromo derivatives by reaction with cuprous cyanide in a suitable solvent.
  • US' 193 describes the C-alkylation reaction of 5-cyanophthalane with 3-NjN'-dimethylaminopropyl chloride using sodium hydride as a base ⁇ n dimethyl sulphoxide (DMSO) medium. 13 volumes of DMSO is used in this reaction with respect to 5-cyanophthalane.
  • DMSO dimethyl sulphoxide
  • Citalopram base is isolated as oil, which is purified by high vacuum distillation (0.03mm at 175-18O 0 C) and then converted into acid addition salts by conventional methods.
  • a main drawback of this process is the need to purify the oily Citalopram base using high vacuum distillation (0.03mm) at 175-18O 0 C. Achieving such a high vacuum at plant level is difficult and apart from these constraints, the process has another drawback in that Citalopram base having a cyano group at the 5 th position of the bicyclic ring system may decompose during high vacuum distillation at high temperature to form Citalopram carboxamide as one of the impurity, resulting in poor quality product and yield.
  • US Patent No.4,650,884 discloses diol of formula (II), 4-[4-(dimethylamino)-l- (4 ' -fluorophenyl)- 1 -hydroxy- 1 -butyl] -3 -(3 -hydroxy methyl)-benzonitrile, its preparation and use as an intermediate in the preparation of Citalopram. Further processes for the preparation of Citalopram by exchange of 5-halogen or CF 3 -(CF 2 ) n - SO 2 -O-, n being 0-8, with cyano are disclosed in WOOOl 1926 and WO0013648.
  • Escitalopram the pharmaceutical activity thereof and crystalline oxalate are disclosed in US Patent no. 4,943,590.
  • Methods for the preparation of Escitalopram along with the disclosure of Escitalopram free base existing as an oil as well as the oxalic, pamoic and L-(+)-tartaric acid addition salts of Escitalopram are disclosed in US'590.
  • the diol is separated into enantiomers by stereo selective crystallization with an enantiomerically pure acid such as (+)-di- J p- toluoyltartaric acid, whereupon the S-enantiomer of the diol is enantioselectively converted to Escitalopram.
  • an enantiomerically pure acid such as (+)-di- J p- toluoyltartaric acid
  • WO 03/087081 discloses the process in which the racemic diol intermediate is treated with optically active acid such as (+)-di-/?-toluoyl tartaric acid to form a diastereiomeric salt. It is subjected to enantiomeric selective cyclization to get 5- substituted Escitalopram, which is replacement of bromine by a nitrile group to get pure optically active acid such as (+)-di-/?-toluoyl tartaric acid to form a diastereiomeric salt. It is subjected to enantiomeric selective cyclization to get 5- substituted Escitalopram, which is replacement of bromine by a nitrile group to get pure
  • the present invention provides a process for the preparation of highly pure Escitalopram or its acid addition salts thereof, which comprises: a) reacting racemic diol or its ester derivative (III) with an optically active acid and at least one solvent to get enantiomerically pure diastereomer (IHA); b) separating the enantiomerically pure diastereomer (IIIA) from its optically active acid salt by treating it with base and followed by stereo selective cyclization; c) separating the Escitalopram base;
  • said optically active acid is selected from the group consisting of tartaric acid, diberizoyl tartaric acid, di-j9-toluoyl tartaric acid, bis-napthyl phosphoric acid, and 10-camphor sulphonic acid.
  • said solvent is selected from the group consisting of lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or any mixture thereof.
  • said base is selected from the group consisting of triethyl amine, alkali metal carbonates, bicarbonates and their hydroxides and liquid ammonia.
  • said stereo selective cyclization is carried out by reacting with methane sulphonyl chloride or p-toluene sulphonyl chloride in presence of a base.
  • a base is triethyl amine.
  • said enantiomerically pure diastereomer (IIIA) is optionally purified in a solvent or a mixture of solvents.
  • said solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate and acetone or mixture thereof.
  • said Escitalopram or its acid addition salt is purified using a mixture of solvents.
  • said mixture of solvents contains at least isopropyl alcohol and one or more of methanol, ethanol, ethyl acetate, acetone or mixtures thereof.
  • said highly pure Escitalopram is optionally converted into its acid addition salt.
  • the Escitalopram or its acid addition salts of the present invention have a chiral purity of 99.5% or greater and HPLC purity of 99.5% or greater.
  • the Escitalopram or its acid addition salts of the present invention have a a chiral purity of 99.5% or greater and HPLC purity of 99% or greater.
  • the Escitalopram or its acid addition salts of the present invention have a a chiral purity of 99% or greater.
  • the disclosed embodiment of the present invention deals with a process for the preparation of highly pure Escitalopram or its acid addition salts thereof of formula (I) according to scheme 4;
  • racemic diol or its ester derivative (III) which comprises: a) reacting racemic diol or its ester derivative (III) with an optically active acid and at least one solvent to get enantiomerically pure diastereomer (IIIA); b) separating the enantiomerically pure diastereomer from its optically active acid salt by treating it with base and followed by stereo selective cyclization; c) separating the Escitalopram base; d) optionally, converting Escitalopram base into its acid addition salt.
  • racemic diol compound of formula III is treated with pure optically active acid in a mixture of solvents to get an enantiomerically pure diol of formula IIIA.
  • the optically active acid used herein is selected from the group consisting of but not limited to tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, bis-napthyl phosphoric acid, and 10-camphor sulphonic acid preferably di-j ⁇ ?-toluoyl tartatic acid.
  • the reaction is carried out in a solvent selected from the group consisting of lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture thereof preferably in a mixture of methanol and isopropyl alcohol.
  • the reaction is carried out firstly at a temperature of 40-60 0 C and then at a temperature of 20-25 0 C for a period of 6-24 hrs.
  • the reaction mixture is then cooled to 0-5 0 C to get the solid material, which is separated by filtration to get a compound of formula IIIA with a chiral purity of greater than 99%.
  • the compound of formula IIIA is optionally purified using a mixture of solvents to get the chiral purity in the range of 99.5-99.8%.
  • the solvent used herein is selected from the group consisting of but not limited to methanol, ethanol, isopropyl alcohol, ethyl acetate and acetone or mixture thereof preferably methanol and isopropyl alcohol or methanol and ethanol.
  • the purification is carried out by dissolving the compound of formula IIIA in a mixture of solvent at a temperature of 40-60 0 C and then cooled to 0- 5 0 C. Solid material is filtered to get the compound of formula IIIA with a chiral purity in the range of 99.5-99.8%.
  • the compound of formula IIIA is treated with base to get converted into a free diol (chirally pure), which is then subjected to stereo selective cyclization to get a compound of formula 11 i.e. Escilalopram base in chirally pure form with chiral purity greater than 99%.
  • the enantiomerically pure optically active acid salt of diol is then converted to optically pure diol by treating with a base in presence of water or optionally in a mixture of water and water immiscible solvent.
  • the base used herein is selected from the group consisting of organic and inorganic base.
  • Organic base are selected from the group of triethyl amine whereas inorganic base are selected from the group of alkali metal carbonates, bicarbonates and their hydroxides and liquid ammonia.
  • the reaction is carried out at a basic pH range of 7.0-9.0 preferably 8.0-8.5 and at a temperature range of O 0 C to room temperature.
  • the resulting solution is then extracted with water immiscible organic solvents to get the optically pure diol compound.
  • the solvent used herein is selected from the group consisting of toluene, chloroform, dichloromethane and dichloroethane preferably dichloromethane.
  • Optically pure diol as such i.e. without isolation is further subjected to stereo selective cyclization by reacting with a methane sulphonyl chloride or p-toluene sulphonyl chloride in presence of triethyl amine and a solvent system i.e. dichloromethane. After completion of the reaction, liquor ammonia is added to the reaction mass and separated the layers. The organic layer is washed with water and extracted with 10-20% aqueous acid.
  • the aqueous acid group is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and acetic acid preferably acetic acid.
  • the aqueous extract is then diluted with water miscible organic solvent.
  • the solvent used herein is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethylsulfoxide preferably isopropyl alcohol.
  • the pH of the resulting solution is adjusted to basic by employing base selected from sodium, potassium hydroxide, and ammonia solution.
  • the preferred base employed to precipitate the Escitalopram base is liquid ammonia.
  • the reaction mass is cooled to 0-5 0 C and the solid is separated by filtration to get crystalline Escitalopram base with a chiral purity in the range of 99.5-99.8%.
  • the crystalline Escitalopram base is then converted to its acid addition salts by reacting it with acid in presence of solvent.
  • the solvent used herein is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran or mixtures thereof preferably isopropyl alcohol.
  • the amount of acid used herein is 1.0 equivalent to the Escitalopram base.
  • the acid used herein is selected from the group consisting of oxalic acid, hydrochloric acid, and hydrobromic acid, preferably oxalic acid.
  • the reaction mixture is stirred for 2-10 hours at 20-25 0 C.
  • the separated acid addition salts are filtered and washed with solvent to get pure Escitalopram acid addition salts.
  • the Escitalopram acid addition salt is further purified by employing simple purification in a solvent.
  • the solvent used herein for purification is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone or mixtures thereof preferably mixture of methanol and ethyl acetate or methanol and isopropyl alcohol.
  • the racemic diol of formula III is prepared according to the process already disclosed in prior art i.e. in WO2005077927. In conclusion, this is an improved, economical and a high yielding process for the industrial production of highly pure Escitalopram base as well as Escitalopram acid addition salts using novel solvent system.
  • Example 1 illustrate specific embodiments of the present invention. They are, however, not intended to limit the scope of present invention in any way.
  • Example 1
  • the crystalline Escitalopram base (21 g) was dissolved in isopropyl alcohol (105mL) at 50-60 0 C.
  • Oxalic acid dihydrate (8.2 g) was added and the mixture was stirred at 50-60 0 C, cooled to 0-5°C, the solid formed was filtered and dried to get
  • the crystalline Escitalopram base (21 g) was dissolved in methanol (105mL) at
  • Oxalic acid dihydrate (8.2 g) was added and the mixture was stirred at 50-
  • Oxalic acid dihydrate (8.2 g) was added and the mixture was stirred at 50-

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un processus de préparation d'escitalopram extrêmement pur ou de ses sels d'addition acides. Ledit processus consiste à (a) faire réagir un diol racémique ou son dérivé d'ester (III) avec un acide actif optiquement et au moins un solvant afin d'obtenir un diastéréomère pur au niveau énantiomère (IIIA), à (b) séparer ledit diastéreomère pur au niveau énantiomère (IIIA) de son sel acide actif optiquement par traitement avec une base, suivi d'une cyclisation stéréosélective, et à (c) séparer la base d'escitalopram.
PCT/IN2006/000124 2005-04-04 2006-04-04 Processus de preparation d'escitalopram ou de ses sels d'addition acides WO2006106531A1 (fr)

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Application Number Priority Date Filing Date Title
EP06728421A EP1877394A1 (fr) 2005-04-04 2006-04-04 Processus de preparation d'escitalopram ou de ses sels d'addition acides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN856/DEL/2005 2005-04-04
IN856DE2005 2005-04-04

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006136169A3 (fr) * 2005-06-22 2007-10-18 Lundbeck & Co As H Base cristalline d'escitalopram et comprimes orodispersible la comprenant
WO2008059514A2 (fr) * 2006-07-31 2008-05-22 Cadila Healthcare Limited Procédé de préparation d'escitalopram
GB2448848A (en) * 2007-09-11 2008-10-29 Lundbeck & Co As H Resolution of escitalopram
EP2017271A1 (fr) * 2007-07-06 2009-01-21 Aurobindo Pharma Limited Procédé de préparation d'escitalopram
US7560576B2 (en) 2005-06-22 2009-07-14 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
US8022232B2 (en) 2007-09-11 2011-09-20 H. Lundbeck A/S Method for manufacture of escitalopram
CN102190600A (zh) * 2010-03-13 2011-09-21 浙江华海药业股份有限公司 一种右旋西酞普兰中间体s-型二醇的制备方法
ITMI20120105A1 (it) * 2012-01-30 2013-07-31 Carthesia S A S Soluzione acquosa di escitalopram ossalato e relativo utilizzo
ITMI20120106A1 (it) * 2012-01-30 2013-07-31 Carthesia S A S Pastiglie liofilizzate di escitalopram ossalato per somministrazione sublinguale
WO2013114416A1 (fr) * 2012-01-30 2013-08-08 Carthesia S.A.S. Comprimés lyophilisés d'oxalate d'escitalopram destinés à être administrés par voie sublinguale
CN103342664A (zh) * 2013-07-18 2013-10-09 山东新华制药股份有限公司 酒石酸盐的制备方法
CN104119248A (zh) * 2014-08-08 2014-10-29 广东东阳光药业有限公司 S-西酞普兰的制备方法
WO2016074225A1 (fr) * 2014-11-14 2016-05-19 浙江华海药业股份有限公司 Procédé de résolution de l'intermédiaire du citalopram 5-cyanogéne diol
WO2016197320A1 (fr) * 2015-06-09 2016-12-15 浙江华海药业股份有限公司 Procédé de préparation d'un intermédiaire glycolé de citalopram
CN106324141A (zh) * 2016-08-30 2017-01-11 山东京卫制药有限公司 一种草酸艾司西酞普兰有关物质的高效液相检测方法
CN106892837A (zh) * 2017-03-23 2017-06-27 浙江师范大学 4‑[4‑(二甲氨基)‑1‑(4‑氟苯基)‑1‑羟丁基]‑3‑羟甲基苯腈的合成
CN108976188A (zh) * 2017-06-05 2018-12-11 上海奥博生物医药技术有限公司 一种艾司西酞普兰双羟萘酸盐新的制备方法
CN110590602A (zh) * 2019-09-25 2019-12-20 浙江海森药业股份有限公司 外消旋西酞普兰二醇的拆分精制方法
CN110873762A (zh) * 2018-09-03 2020-03-10 万全万特制药江苏有限公司 Hplc法测定西酞普兰中间体及其有关物质的方法
KR20200032281A (ko) * 2018-09-17 2020-03-26 (주)유케이케미팜 카보네이트를 이용한 시탈로프람 및 에스시탈로프람의 새로운 제조 방법

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WO2004065375A1 (fr) * 2003-01-17 2004-08-05 Natco Pharma Limited Procede de preparation d'escitalopram et de son precurseur
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WO2006025071A1 (fr) * 2004-09-02 2006-03-09 Natco Pharma Limited Procédé de synthèse de l'escitalopram

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Cited By (58)

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Publication number Priority date Publication date Assignee Title
WO2006136169A3 (fr) * 2005-06-22 2007-10-18 Lundbeck & Co As H Base cristalline d'escitalopram et comprimes orodispersible la comprenant
JP2012072168A (ja) * 2005-06-22 2012-04-12 H Lundbeck As エスシタロプラムの結晶質塩基、およびエスシタロプラム塩基を含む口腔内分散性錠剤
AU2006261452B2 (en) * 2005-06-22 2010-02-04 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
GB2448834A (en) * 2005-06-22 2008-10-29 Lundbeck & Co As H Preparation of salts of escitalopram from precipitated escitalopram free base
EA019239B1 (ru) * 2005-06-22 2014-02-28 Х. Лундбекк А/С Кристаллическое свободное основание эсциталопрама и фармацевтическая композиция, содержащая свободное основание эсциталопрама
GB2448834B (en) * 2005-06-22 2010-01-20 Lundbeck & Co As H Preparation of salts of escitalopram
GB2442160A (en) * 2005-06-22 2008-03-26 Lundbeck & Co As H Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
GB2442160B (en) * 2005-06-22 2010-01-20 Lundbeck & Co As H Preparation of escitalopram free base and salts
US7723533B2 (en) 2005-06-22 2010-05-25 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
EP2325177A1 (fr) * 2005-06-22 2011-05-25 H. Lundbeck A/S Base cristalline de l'escitalopram
US7560576B2 (en) 2005-06-22 2009-07-14 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
US7834201B2 (en) 2005-06-22 2010-11-16 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
WO2008059514A3 (fr) * 2006-07-31 2009-04-02 Cadila Healthcare Ltd Procédé de préparation d'escitalopram
WO2008059514A2 (fr) * 2006-07-31 2008-05-22 Cadila Healthcare Limited Procédé de préparation d'escitalopram
EP2017271A1 (fr) * 2007-07-06 2009-01-21 Aurobindo Pharma Limited Procédé de préparation d'escitalopram
TWI391383B (zh) * 2007-09-11 2013-04-01 Lundbeck & Co As H 製造艾司西酞普蘭（ｅｓｃｉｔａｌｏｐｒａｍ）之方法
GB2448848A (en) * 2007-09-11 2008-10-29 Lundbeck & Co As H Resolution of escitalopram
CY2600B1 (en) * 2007-09-11 2010-03-03 Lundbeck & Co As H Method for manufacture of escitalopram
AU2008212055B2 (en) * 2007-09-11 2010-08-12 H. Lundbeck A/S Method for manufacture of escitalopram
EA012787B1 (ru) * 2007-09-11 2009-12-30 Х. Лундбекк А/С Способ получения эсциталопрама
GB2448848B (en) * 2007-09-11 2011-01-26 Lundbeck & Co As H Method for manufacture of escitalopram
JP2009149600A (ja) * 2007-09-11 2009-07-09 H Lundbeck As エスシタロプラムの製造方法
AU2008212055C1 (en) * 2007-09-11 2011-06-02 H. Lundbeck A/S Method for manufacture of escitalopram
KR101054224B1 (ko) 2007-09-11 2011-08-08 하. 룬트벡 아크티에 셀스카브 에스시탈로프람의 제조 방법
US8022232B2 (en) 2007-09-11 2011-09-20 H. Lundbeck A/S Method for manufacture of escitalopram
ES2334875A1 (es) * 2007-09-11 2010-03-16 H. Lundbeck A/S Metodo para preparar escitalopram.
EP2397461A1 (fr) * 2007-09-11 2011-12-21 H. Lundbeck A/S Procédé de fabrication d'escitalopram
NL2001953C2 (en) * 2007-09-11 2009-05-07 Lundbeck & Co As H Method for manufacture or escitalopram.
WO2009033488A1 (fr) * 2007-09-11 2009-03-19 H. Lundbeck A/S Procede de fabrication d'escitalopram
CN102190600B (zh) * 2010-03-13 2015-04-15 浙江华海药业股份有限公司 一种右旋西酞普兰中间体s-型二醇的制备方法
CN102190600A (zh) * 2010-03-13 2011-09-21 浙江华海药业股份有限公司 一种右旋西酞普兰中间体s-型二醇的制备方法
ITMI20120105A1 (it) * 2012-01-30 2013-07-31 Carthesia S A S Soluzione acquosa di escitalopram ossalato e relativo utilizzo
WO2013114416A1 (fr) * 2012-01-30 2013-08-08 Carthesia S.A.S. Comprimés lyophilisés d'oxalate d'escitalopram destinés à être administrés par voie sublinguale
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