[go: up one dir, main page]

WO2007007347A1 - Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires - Google Patents

Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires Download PDF

Info

Publication number
WO2007007347A1
WO2007007347A1 PCT/IN2005/000241 IN2005000241W WO2007007347A1 WO 2007007347 A1 WO2007007347 A1 WO 2007007347A1 IN 2005000241 W IN2005000241 W IN 2005000241W WO 2007007347 A1 WO2007007347 A1 WO 2007007347A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
methanol
fexofenadine
ketone
mixture
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/IN2005/000241
Other languages
English (en)
Inventor
Siddiqui Mohammed Jaweed Mukarram
Aravind Yekanathsa Merwade
Anjum Reyaz Khan
Pawan Vrajlal Solanki
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.)
Wockhardt Ltd
Original Assignee
Wockhardt 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 Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of WO2007007347A1 publication Critical patent/WO2007007347A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to the robust, economically feasible and environmentally friendly manufacturing process of Anhydrous Fexofenadine Hydrochloride (I) with controlled level of side products.
  • Anhydrous Fexofenadine Hydrochloride (I) with controlled level of side products.
  • the second aspect of the present invention is to furnish Fexofenadine Hydrochloride with controlled level of water content, i.e., not more than 0.5% using acetone as a solvent of choice for dehydration.
  • the present invention relates to a purification method of the crude product to get acceptable quality of Fexofenadine Hydrochloride.
  • the present invention reports the robust manufacturing process for the production of Fexofenadine Hydrochloride having less than 1.0% of total impurities and moisture content less than 0.5 % .
  • the characterization of the known impurities, i.e. , Fexofenadone and meta- isomer of Fexofenadine has been done by IR, NMR ( 1 H and C 13 ), LC MS MS and HPLC impurity profile gradient method.
  • the manufacturing process starts from the ⁇ , ⁇ -Dimethylphenyl acetic acid.
  • ⁇ , ⁇ - Dimethylphenyl acetic acid on treatment with methanol in presence of concentrated sulfuric acid in catalytic amount provides the methyl ester of ⁇ , ⁇ -Dirnethylphenyl acetic acid, i.e., methyl- ⁇ , ⁇ -Dimethylphenyl acetate .
  • the Fexofenadone methyl ester is reduced with sodium borohydride in methanol, which on subsequent alkaline hydrolysis in water methanol mixture gives Fexofenadine having para and meta isomer.
  • the present invention relates to a process for the efficient purification method of Fexofenadine and its hydrochloride salt having less than 1.0% of total impurities and moisture content less than 0.5%.
  • the characterization of the known impurities, i.e., Fexofenadone and meta-isomer of Fexofenadine has been done by IR, NMR ( 1 H and C 13 ), LC MS MS and HPLC impurity profile gradient method.
  • the present invention is directed to a manufacturing process of 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]- ⁇ , ⁇ - dimethylbenzene acetic acid hydrochloride in pure form.
  • the schematic presentation of synthetic process of fexofenadine hydrochloride is shown in Scheme I.
  • Fexofenadine hydrochloride Anhydrous Fexofenadine hydrochloride
  • crude fexofenadine metal and para isomers
  • Methyl- ⁇ , ⁇ -dimethylphenylacetic acid on Fridel-Craft's acylation with 4-chlorobutyryl chloride in presence of anhydrous aluminum chloride in ethylene dichloride produced acylated Methyl- ⁇ , ⁇ -dimethylphenyl acetic acid, i.e., ketone intermediate as meta and para- isomers.
  • Methyl-4-(4-chloro-l-oxobutyryl)- ⁇ , ⁇ -dimethyl ⁇ henyl acetate (Ketone) (meta and para isomers) was dissolved in toluene followed by addition of Azacyclanol and water in presence of potassium carbonate and potassium iodide. Reaction mixture was refluxed for about 30 to 40 hours. After the reaction was completed, reaction mixture was cooled to room temperature and aqueous layer was discarded.
  • Methyl-4-(4-Chloro-l-oxobutyryl)- ⁇ , ⁇ -dimethylphenyl acetate, (Ketone) (meta and para isomers) was dissolved in dimethyl formamide followed by addition of Azacyclnol, potassium carbonate and potassium iodide.
  • the reaction mixture was heated at 90 18 C for about 7 to 12 hours. Reaction was monitored by HPLC. After the reaction was completed it was cooled to room temperature and the product was extracted with chloroform and was well washed with water. Removal of the organic solvent at reduced pressure yielded thick oily carbinol.
  • Methyl-4 ⁇ 4-[4-(hydroxydiphenylmetyl)-l-piperidinyl ⁇ -l-hydroxybutyl]- ⁇ , ⁇ - dimethylbenzene acetate (carbinol) obtained as oily mass in example 3 was dissolved in methanol and cooled to about 0 to 20 ® C followed by addition of sodium borohydride. At the same temperature reaction mass stirred for 2 to 5 hours. After the reduction was completed the reaction mass was stirred at room temperature in presence of water and chloroform. Organic layer was separated followed by rewashing with aqueous layer.
  • the dicarbinol prepared in example 3 was dissolved in methanol followed by addition of sodium hydroxide in potable water followed by refluxed for about 3 to 6 hours. Methanol was distilled off, once the reaction deprotection was completed. The reaction mixture was cooled to room temperature and to it chloroform was added. Reaction mixture was cooled to about 0 to 2O 0 C. pH of the reaction mass was adjusted to about 6.4 to 6.8 with 50 % aqueous hydrochloric acid solution. Reaction mixture was stirred for 1 hour at the same pH. Chloroform was separated and aqueous layer was washed twice with chloroform. Organic layer was pooled and submitted for distillation under reduced pressure.
  • Fexofenadine (40 Kg) thus isolated from the above step was charged to about 60 to 100 Ltr of a mixture of methanol in methylethyl ketone in volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol in methylethyl ketone was 0.4 to 2.0, specifically about 0.4 to 0.6.
  • the reaction mass was refluxed for about 10 minutes to 2 hours, more particularly between about 20 minutes to 40 minutes. After the said time reaction mass was cooled to room temperature followed by stirring for another 1 hour at room temperature. The reaction mixture was centrifuged. The same treatment was repeated twice followed by treatment with dimethyl formamide-methanol and water.
  • Three times treated fexofenadine base in the above step was charged to about 120 to 180 Ltr of a mixture of methanol in DMF volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol was 0.4 to 2.0. More particularly, the volume ratio of methanol in DMF was about 0.4 to 0.6.
  • the reaction mixture was refluxed for about 10 minutes to 2 hours, more particularly between about 30 minutes to 1.5 hours. After the said time reaction mixture was cooled to room temperature and centrifuged.
  • Fexofenadine base having moisture content about 2.5 to 6% was taken in methanol and treated with 50 % aqueous HCl to make the pH of the solution between 2.4 to 2.6.
  • the clear solution was filtered to remove any solid contaminant.
  • Chilled potable water was added to the solution at 0 to 20°C.
  • the hydrochloride salt of fexofenadine was obtained as white crystals. Additional volume of water was added to the reaction mixture at the same temperature and stirred for 2 hours. Material was centrifuged and dried.
  • the fexofenadine hydrochloride obtained in the above step was treated with acetone for about 30 minutes to 2 hours between about 4O 0 C to reflux temperature.
  • the reaction mixture was cooled to 0 to 5°C and centrifuged. Centrifuged material was dried in FBD for 6 to 8 hours at 60 to 8O 0 C to get the title product having moisture content between about 0.2 to 0.5% .
  • Methyl-4-(4-chloro-l-oxobutyryl)- ⁇ , ⁇ -dimethyl phenyl acetate (Ketone) 70 Kg (0.2482 Kmole) was dissolved in 500 to 700 Ltr toluene and to it was added Azacyclanol, 50 to 60 Kg followed by potassium bicarbonate, 74 Kg (0.7391 Kmole) and potassium iodide, 0.50 to 1.20 Kg. Finally, to it was added 53 Ltr water. Reaction mixture was refluxed for 30 to 40 Hours. Completion of the reaction was monitored by HPLC. On completion the reaction mixture was cooled to room temperature and aqueous layer was discarded. Toluene layer was filtered through Nutsche. Finally toluene was distilled under reduced pressure and degassed for 2 hours to get the oily mass of carbinol.
  • Carbinol (Methyl-4 ⁇ 4-[4-(hydroxydiphenyhnetyl)-l-piperidinyl ⁇ -l-oxobutyl]-a, a- dimethylbenzene acetate)
  • Reaction mixture was heated at 9O 0 C for 7 to 2 Hours. Completion of the reaction was monitored by HPLC. On completion the reaction mixture was cooled to room temperature and the product was extracted twice with chloroform and finally washed with water. Removal of the solvent at reduced pressure provides thick oily carbinol.
  • Fexofenadine base obtained after third purification was treated with a mixture of 100 Ltr dimethylformamide and 50 Ltr methanol and heated at reflux for an hour. Then cooled to room temperature and centrifuged.

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation du chlorhydrate de fexofénadine anhydre avec un taux minimum de produits secondaires. Un autre aspect de la présente invention concerne la purification d’une base de fexofénadine dépourvue d'isomère méta de la base de fexofénadine et de fexofénadinone.
PCT/IN2005/000241 2005-07-07 2005-07-13 Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires Ceased WO2007007347A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN809MU2005 2005-07-07
IN809/MUM/2005 2005-07-07

Publications (1)

Publication Number Publication Date
WO2007007347A1 true WO2007007347A1 (fr) 2007-01-18

Family

ID=37636776

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000241 Ceased WO2007007347A1 (fr) 2005-07-07 2005-07-13 Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires

Country Status (1)

Country Link
WO (1) WO2007007347A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride
WO2009136412A3 (fr) * 2008-04-25 2010-03-25 Matrix Laboratories Limited Processus pour la préparation d’ester méthylique d’acide acétique 4-[4-(4-(hydroxydiphénylméthyl)- 1-pipéridinil]-1-oxobutyl]-α,α-diméthylbenzène et son utilisation
WO2009034582A3 (fr) * 2007-09-13 2010-05-06 Ind-Swift Laboratories Limited Procédé pour la préparation de chlorhydrate de fexofénadine amorphe
CN102070512A (zh) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 一种高纯度非索非那定及其中间体的合成路线与制备方法
CN102070490A (zh) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 一种非索非那定中间体2-(4-(4-羟基丁酰基)苯基)-2-甲基丙氰的制备方法
JP2012087100A (ja) * 2010-10-21 2012-05-10 Sumitomo Chemical Co Ltd 形態ｉのフェキソフェナジン一塩酸塩の製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002102777A2 (fr) * 2001-06-18 2002-12-27 Dr. Reddy's Laboratories Ltd. Nouvelles formes cristallines d'acide 4-[4-[4-(hydroxydiphenylmethyl)-1-piperindinyl]-1-hydroxybutyl]-$g(a)-$g(a)- dimethylbenzene acetique et son chlorhydrate
US6797826B2 (en) * 1993-06-24 2004-09-28 Amr Technology, Inc. Piperidine derivatives and process for their production
US6903232B2 (en) * 2001-06-25 2005-06-07 Aurobindo Pharma Ltd. Process for the preparation of a highly pure pharmaceutical intermediate, 4-(cyclopropylcarbonyl)-α, α-dimethylphenylacetic acid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6797826B2 (en) * 1993-06-24 2004-09-28 Amr Technology, Inc. Piperidine derivatives and process for their production
WO2002102777A2 (fr) * 2001-06-18 2002-12-27 Dr. Reddy's Laboratories Ltd. Nouvelles formes cristallines d'acide 4-[4-[4-(hydroxydiphenylmethyl)-1-piperindinyl]-1-hydroxybutyl]-$g(a)-$g(a)- dimethylbenzene acetique et son chlorhydrate
US6903232B2 (en) * 2001-06-25 2005-06-07 Aurobindo Pharma Ltd. Process for the preparation of a highly pure pharmaceutical intermediate, 4-(cyclopropylcarbonyl)-α, α-dimethylphenylacetic acid

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride
WO2009034582A3 (fr) * 2007-09-13 2010-05-06 Ind-Swift Laboratories Limited Procédé pour la préparation de chlorhydrate de fexofénadine amorphe
WO2009136412A3 (fr) * 2008-04-25 2010-03-25 Matrix Laboratories Limited Processus pour la préparation d’ester méthylique d’acide acétique 4-[4-(4-(hydroxydiphénylméthyl)- 1-pipéridinil]-1-oxobutyl]-α,α-diméthylbenzène et son utilisation
CN102070512A (zh) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 一种高纯度非索非那定及其中间体的合成路线与制备方法
CN102070490A (zh) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 一种非索非那定中间体2-(4-(4-羟基丁酰基)苯基)-2-甲基丙氰的制备方法
CN102070490B (zh) * 2009-11-21 2014-07-30 浙江华海药业股份有限公司 一种非索非那定中间体2-(4-(4-羟基丁酰基)苯基)-2-甲基丙氰的制备方法
CN102070512B (zh) * 2009-11-21 2014-11-19 浙江华海药业股份有限公司 一种高纯度非索非那定及其中间体的合成路线与制备方法
JP2012087100A (ja) * 2010-10-21 2012-05-10 Sumitomo Chemical Co Ltd 形態ｉのフェキソフェナジン一塩酸塩の製造方法

Similar Documents

Publication Publication Date Title
JP4996467B2 (ja) Ｎ−（４−フルオロベンジル）−ｎ−（１−メチルピペリジン−４−イル）−ｎ’−（４−（２−メチルプロピルオキシ）フェニルメチル）カルバミド、並びにその酒石酸塩及び結晶形態の合成
JP5503546B2 (ja) ４，５−ジメトキシ−１−（メチルアミノメチル）−ベンゾシクロブタンの分離
JP2008094848A (ja) 新規な型の４−［４−［４−（ヒドロキシジフェニルメチル）−１−ピペリジニル］−１−ヒドロキシブチル］−α，α−ジメチルベンゼン酢酸及びその塩酸塩
US20160297825A1 (en) Efficient method for the preparation of tofacitinib citrate
WO2007007347A1 (fr) Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires
JP4344230B2 (ja) ピペリジン誘導体フェキソフェナジンの製造方法
JP5585822B2 (ja) 光学活性ニペコチン酸誘導体の製造方法
EP2507212B1 (fr) Procédé de préparation de chlorhydrate de phénidate de méthyle
AU2001278094A1 (en) Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperindinyl]-1-hydroxybutyl]-alpha, alpha-dimethylbenzene acetic acid and its hydrochloride
JP2009515945A (ja) 塩酸ドネペジルの調製に有用な中間体およびその新規な多形の改善された合成および調製
WO2014009964A1 (fr) Procédé d'enrichissement énantiomerique de 2', 6'-pipécoloxylidide
WO2011161646A2 (fr) Procédé de préparation d'alvimopan ou de son sel ou solvate pharmaceutiquement acceptable
JP2003515600A (ja) ｛２−［４−（α−フェニル−ｐ−クロロベンジル）ピペラジン−１−イル］エトキシ｝酢酸の製法及びそのための新規な中間体
JP5714748B2 (ja) ビフェニル−２−イルカルバミン酸エステルの調製方法
US20020082277A1 (en) Tosylate salts of 4-(p-fluorophenyl)-piperidine -3-carbinols
CN100475774C (zh) D-（+）-或l-（-）-酒石酸或其衍生物作为dl-麻黄碱或其衍生物的拆分剂及其拆分方法
CN115448871B (zh) 一种盐酸替罗非班的制备方法
CN100404543C (zh) 一种合成吡利霉素的中间体及其制备方法和用途
KR100954755B1 (ko) (ｒ)-(-)-1-[(4-클로로페닐)페닐메틸]피페라진의 제조방법
JP2002371060A (ja) 光学活性アミノピペリジン誘導体の製造方法
CA2588777C (fr) Nouveaux procedes de preparation de formes cristallines du chlorhydrate de sertaline
CN115960036A (zh) 一种(r)-3-氨基哌啶二盐酸盐的制备方法
WO2007052310A2 (fr) Polymorphes d'hydrochlorure de fexofenadine et processus de preparation de ceux-ci
WO2007025696A2 (fr) Fabrication de composes substitues piperazinyle
CN113121414A (zh) 一种曲格列汀中间体的合成方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

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

Ref document number: 05815852

Country of ref document: EP

Kind code of ref document: A1