WO2009157006A1 - Procédé de préparation de l'ébastine - Google Patents

Procédé de préparation de l'ébastine Download PDF

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Publication number
WO2009157006A1
WO2009157006A1 PCT/IN2008/000504 IN2008000504W WO2009157006A1 WO 2009157006 A1 WO2009157006 A1 WO 2009157006A1 IN 2008000504 W IN2008000504 W IN 2008000504W WO 2009157006 A1 WO2009157006 A1 WO 2009157006A1
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WO
WIPO (PCT)
Prior art keywords
ebastine
solvent
organic solvent
reaction
ethyl acetate
Prior art date
Application number
PCT/IN2008/000504
Other languages
English (en)
Inventor
Thirupalu M Reddy
Chittibabu N
Srinivasa P Reddy
Phanikumar B Reddy
Cheluvaraju
Madhusudana G Rao
Original Assignee
Micro Labs 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 Micro Labs Limited filed Critical Micro Labs Limited
Publication of WO2009157006A1 publication Critical patent/WO2009157006A1/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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4

Definitions

  • This invention relates to a novel process for the preparation of ebastine.
  • the invention also relates to process of preparation of 1-[4-(1 , 1 -dimethyl ethyl) phenyl]- 4-(4-hydroxy piperidin-1-yl) butan-1-one (compound II), an intermediate or preparation of ebatine
  • Ebastine 1-[4-(1 ,1-Dimethylethyl)-phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone, commonly known as Ebastine.
  • Ebastine is discovered and developed by Fordonal. The structure of ebastine is given below.
  • Ebastine is generally prepared from 1-[4-(1 , 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one and diphenyl methyl bromide.
  • Several methods for the preparation ebastine are known in literature.
  • the above-disclosed scheme has several disadvantages, which are as follows:
  • the compound (II) is purified in the form of fumarate salt and further it reacts with compound (III).
  • the compound (III) is highly unstable and moisture sensitive. More over the compound (III) is costlier. Also the process requires refluxing the reaction mixture for more than 36 hours with addition of compound (III) at every 12 hours time interval.
  • An object of the present invention is to provide a process of preparing ebastine.
  • Another object of the present invention is to provide a process of preparing ebastine wherein the process requires about 6 hours time.
  • the present invention is to provide a process of preparing pure ebastine with purity not less than 99.6 %.
  • Another object is to provide a process for preparation of compound Il which is an intermediate for formation of ebastine.
  • a process for preparation of ebastine comprising reaction of 1-[4-(1 , 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one compound (II) and diphenyl methanol in presence of dehydrating agent in organic solvent system to obtain ebastine fumarate salt (compound IV) in organic solvent.
  • the present invention relates to an efficient and cost effective method of synthesis of ebastine comprising the preparation of 1-[4-(1 , 1-dimethyl ethyl) phenyl]-4-(4- hydroxy piperidin-1-yl) butan-1-one by reacting 1 -(4-terf-butylphenyl)-4- chlorobutan-1-one and 4-hydroxy piperidine in organic solvent system in basic condition in one aspect and refluxing the 1-[4-(1 , 1-dimethyl ethyl) phenyl]-4-(4- hydroxy piperidin-1-yl) butan-1-one thus obtained with diphenyl methanol in presence of dehydrating agent by removing the generated water as an azeotrope in another aspect.
  • the crude ebastine is purified by making fumarate salt.
  • the Ebastine fumarate salt is suspended in organic solvent in presence of base stirred for 30 minutes and organic layer is separated. Distilled out solvent completely under vacuum and crystallize
  • the present invention relates to a novel process for preparing ebastine that eliminates the disadvantages of prior art processes for the synthesis of 1- [4-(1 , 1- dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (II) and also eliminate extensive purification requirements.
  • the present invention provides a process of preparing the ebastine, which has following synthetic scheme:
  • the coupling reaction between compound (I) and 4-hydroxy piperidine is carried out in presence of a base in organic solvent system, wherein organic solvent is selected from water miscible solvent such as acetonitrile, dioxane. N, N-dimethyl formamide, acetone etc and water immiscible solvent such as toluene, methyl isobutyl ketone, dichlomethane, xylene, chloroform, cyclohexane and mixtures thereof.
  • the reaction is carried out in the presence of toluene.
  • the base employed can be selected from organic and inorganic bases.
  • the organic base can be selected from alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate and metal hydroxides such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • the organic base can be selected from triethylamine, diisopropyl ethylamine or pyridine.
  • the preferred base is sodium bicarbonate.
  • the reaction can be carried out from ambient temperature to reflux temperature of the solvent and it generally takes 6-12 hours to go to completion. Typically the reaction is carried out at refluxing temperature of the solvent for about 6-8hours.
  • the solvent is distilled out under vacuum and the resulting residue is dissolved in ethyl acetate and water.
  • the organic layer pH is adjusted to acidic with mineral acids such as hydrochloric acid, sulphuric acid or acetic acid. The preferred pH is 2-3 and preferred acid is HCI.
  • acidic pH the aqueous layer is washed with organic solvent to remove impurities, the desired product is obtained from a mixture of ethyl acetate and n-Hexane directly without any further purification.
  • ebastine can be prepared by refluxing compound (II) with diphenyl methyl bromide or chloride in presence of sodium carbonate.
  • compound (II) and diphenyl methanol are reacted in presence of dehydrating agent in organic solvent system, wherein organic solvent can be selected from high boiling solvent such as toluene, xylene, methyl isobutyl ketone or dichloroethane.
  • organic solvent can be selected from high boiling solvent such as toluene, xylene, methyl isobutyl ketone or dichloroethane.
  • the preferred solvent is toluene.
  • the dehydrating agent can be selected from p-toluene sulphonic acid monohydrate (PTSA), sulphuric acid, methane sulphonic acid, phosphorous pentoxide, titanium tetrachloride or Dicyclohexylcarbodiimide (DCC) etc.
  • the preferred dehydrating agent is p-toluene sulphonic acid monohydrate.
  • the reaction can be carried out at refluxing temperature of the solvent to remove water as an azeotrope for about 6-16 hours. Preferably 6-8 hours. After the reaction has proceeded to a desired stage as judged by HPLC analysis.
  • the desired compound (IV) is isolated in the form fumarate salt in organic solvent.
  • the organic solvent can be selected from alcohols such as methanol, ethanol or isoproppanol; nitriles such as acetonitrile or propionitrile; esters such as ethyl acetate, propyl acetate or butyl acetate; toluene, methyl isobutyl ketone and mixtures thereof.
  • the preferred solvent is ethyl acetate.
  • a pure ebastine is obtained by breaking ebastine fumarate salt (IV) using base.
  • the base is selected from alkali metal hydroxides, carbonates or bicarbonates, ammonia, tertiary amines and mixtures thereof.
  • the preferred base is sodium hydroxide.
  • a pure ebastine is crystallized from resulting residue obtained from breaking ebastine fumarate salt (IV) in presence of organic solvent at -5 to +25° C.
  • the organic solvent is selected from CrC 6 alcohols such as methanol, ethanol, and propanol; hexanes, cyclohexane; diisopropyl ether and mixtures thereof.
  • the preferred solvent is methanol.
  • the present invention can be illustrated in one of its embodiments by the following non-limiting examples.
  • a mixture of 4-hydroxy piperidine (10.2g, 0.1 mol), 1 -(4-terf-butylphenyl)-4- chlorobutan-1-one (24.1g, 0.1 mol) and triethyl amine (20.2g, 0.2mol) in methyl isobutyl ketone (100ml) is refluxed for 6-8hrs.
  • the progress of the reaction is monitored by HPLC.
  • the reaction mass is cooled to room temperature and washed with water.
  • the organic layer pH is adjusted to 2-3 with 3N HCI solution; the aqueous layer is washed with methyl isobutyl ketone and makes the aqueous solution alkaline with aqueous sodium hydroxide and extracted with ethyl acetate.
  • the ebastine fumarate salt (24Og) is suspended in ethyl acetate (900ml) and 10% sodium hydroxide solution (800ml), stirred for O. ⁇ hours at room temperature to get a clear solution. Separate the organic layer and wash with water till pH comes to neutral. Distill out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure ebastine solid is filtered and dried at 60 - 65 0 C. Yield: 15Og (64%); Melting point: About 86°C.Purity by HPLC: 99.9%
  • the ebastine fumarate salt (20Og) is suspended in ethyl acetate (800ml) and 10% sodium hydroxide solution (700ml), stirred for O. ⁇ hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distill out solvent completely under vacuum and crystallize the resulting residue is from methanol. The obtained pure ebastine solid is filtered and dried at
  • the resulting residue is refluxed with ethyl acetate and fumaric acid (14.3g, 0.12mol).
  • the obtained ebastine fumarate salt is filtered, washed with ethyl acetate and dried at 80-85 0 C.
  • the ebastine fumarate salt (25g) is suspended in ethyl acetate (150ml) and 10% sodium hydroxide solution (100ml), stirred for O. ⁇ hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distill out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure Ebastine solid is filtered and dried at 60 - 65 0 C. Yield: 12g (31%); Melting point: About 86 0 C. Purity by HPLC: 99.7%
  • the ebastine fumarate salt (14Og) is suspended in ethyl acetate (500ml) and 10% sodium hydroxide solution (350ml), stirred for O. ⁇ hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distilled out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure ebastine solid is filtered and dried at 60 - 65 0 C. Yield: 75 g (48%); Melting point: About 86 0 C. Purity by HPLC: 99.9%

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

Abstract

La présente invention porte sur un nouveau procédé de préparation de l'ébastine à partir de la 1-[4-(1,1-diméthyléthyl)phényl]-4-(4-hydroxy-pipéridin-1-yl)butan-1-one et de diphényle méthanol, qui est facilement reproductible à l'échelle industrielle. L'invention porte également sur un procédé de préparation de la 1-[4-(1,1-diméthyléthyl)phényl]-4-(4-hydroxy-pipéridin-1-yl)butan-1-one.
PCT/IN2008/000504 2008-06-26 2008-08-11 Procédé de préparation de l'ébastine WO2009157006A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1560CH2008 2008-06-26
IN1560/CHE/2008 2008-06-26

Publications (1)

Publication Number Publication Date
WO2009157006A1 true WO2009157006A1 (fr) 2009-12-30

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PCT/IN2008/000504 WO2009157006A1 (fr) 2008-06-26 2008-08-11 Procédé de préparation de l'ébastine

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PT (1) PT2009157006W (fr)
WO (1) WO2009157006A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2371817A1 (fr) 2010-04-01 2011-10-05 Arevipharma GmbH Procédé pour la préparation de 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone et de sels d'addition acides correspondant
WO2012076919A1 (fr) * 2010-12-11 2012-06-14 Micro Labs Limited Procédé de préparation de l'ebastine
CN104101663A (zh) * 2014-08-01 2014-10-15 江苏联环药业股份有限公司 用高效液相色谱法测定依巴斯汀有关物质的方法
CN114671802A (zh) * 2022-04-14 2022-06-28 江苏联环药业股份有限公司 一种高纯度依巴斯汀的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550116A (en) 1983-08-05 1985-10-29 Fordonal, S.A. Piperidine derivatives
EP0529365A1 (fr) * 1991-08-08 1993-03-03 Kaken Pharmaceutical Co., Ltd. Dérivés de diarylméthoxypipéridine
WO2004096763A1 (fr) * 2003-05-01 2004-11-11 Vernalis Research Limited Derives d'azetidinecarboxamide et leur utilisation dans le traitement de troubles medies par les recepteur cb1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550116A (en) 1983-08-05 1985-10-29 Fordonal, S.A. Piperidine derivatives
EP0529365A1 (fr) * 1991-08-08 1993-03-03 Kaken Pharmaceutical Co., Ltd. Dérivés de diarylméthoxypipéridine
WO2004096763A1 (fr) * 2003-05-01 2004-11-11 Vernalis Research Limited Derives d'azetidinecarboxamide et leur utilisation dans le traitement de troubles medies par les recepteur cb1

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2371817A1 (fr) 2010-04-01 2011-10-05 Arevipharma GmbH Procédé pour la préparation de 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone et de sels d'addition acides correspondant
WO2011121099A2 (fr) 2010-04-01 2011-10-06 Arevipharma Gmbh Procédé pour la préparation de la 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone et de sels d'addition acide de celle-ci
WO2011121099A3 (fr) * 2010-04-01 2012-03-08 Arevipharma Gmbh Procédé pour la préparation de la 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone et de sels d'addition acide de celle-ci
DE112011101112T5 (de) 2010-04-01 2013-01-10 Arevipharma Gmbh Verfahren zur Herstellung von 1-[4-(1,1-Dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanon und Säureadditionssalzen davon
WO2012076919A1 (fr) * 2010-12-11 2012-06-14 Micro Labs Limited Procédé de préparation de l'ebastine
CN104101663A (zh) * 2014-08-01 2014-10-15 江苏联环药业股份有限公司 用高效液相色谱法测定依巴斯汀有关物质的方法
CN104101663B (zh) * 2014-08-01 2015-10-14 江苏联环药业股份有限公司 用高效液相色谱法测定依巴斯汀有关物质的方法
CN114671802A (zh) * 2022-04-14 2022-06-28 江苏联环药业股份有限公司 一种高纯度依巴斯汀的制备方法
CN114671802B (zh) * 2022-04-14 2024-05-17 江苏联环药业股份有限公司 一种高纯度依巴斯汀的制备方法

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