[go: up one dir, main page]

WO2005019173A1 - Procede de production de sel de tert-butylamine de perindopril pur - Google Patents

Procede de production de sel de tert-butylamine de perindopril pur Download PDF

Info

Publication number
WO2005019173A1
WO2005019173A1 PCT/IN2003/000276 IN0300276W WO2005019173A1 WO 2005019173 A1 WO2005019173 A1 WO 2005019173A1 IN 0300276 W IN0300276 W IN 0300276W WO 2005019173 A1 WO2005019173 A1 WO 2005019173A1
Authority
WO
WIPO (PCT)
Prior art keywords
perindopril
butylamine
tert
salt
process according
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/IN2003/000276
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Matta Ramakrishna Reddy
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.)
Hetero Drugs Ltd
Original Assignee
Hetero Drugs 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 Hetero Drugs Ltd filed Critical Hetero Drugs Ltd
Priority to PCT/IN2003/000276 priority Critical patent/WO2005019173A1/fr
Priority to AU2003263584A priority patent/AU2003263584A1/en
Publication of WO2005019173A1 publication Critical patent/WO2005019173A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a process for obtaining pure perindopril tert-butylamine salt.
  • (2S,3aS,7aS)-1-[(2S)-2-[[(1 S)-1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid and its tert-butylamine salt are angiotensin-converting enzyme inhibitors.
  • the therapeutic uses of perindopril and related compounds and their preparations are disclosed in US 4,508,729 and US 4,914,214.
  • US 4,914,214 describes an industrial process for preparation of perindopril and perindopril tert-butylamine salt. According to US 4,914,214 benzyl ester of formula
  • WO 0158868 describes a process for preparation of perindopril and perindopril tert-butylamine salt. According to WO 0158868 toluenesulfonate of compound of formula
  • perindopril benzyl ester which is hydrogenated and converted into perindopril tert-butylamine salt.
  • the process controls the formation of the impurities of formula VII and VIII. This process also suffers from drawbacks since the process requires strict control of quantities of reactants and is unable to remove other common impurities such as those of formula II to VI.
  • impurities can be isolated from perindopril by extracting an aqueous solution of perindopril or its salt contaminated with impurities with a suitable organic solvent under suitable conditions. The impurities remain in the aqueous phase and perindopril extracted into the organic phase is then converted to pure perindopril tert-butylamine salt.
  • the novel method provides a simple and economical process for obtaining pure perindopril tert-butylamine salt and since perindopril tert-butylamine salt obtained is with high purity, the product can be used in pharmaceutical preparations.
  • SUMMARY OF THE INVENTION The present invention provides a simple process for obtaining substantially pure perindopril tert-butylamine. Impurities that are commonly associated with perindopril are:
  • a process for obtaining substantially pure perindopril tert-butylamine salt which comprises the steps of: a) extracting an aqueous solution of impure perindopril or an impure perindopril salt with an organic solvent selected from methylenedichloride, chloroform, ethylenedichloride, toluene, heptane and a mixture thereof at pH 4.0 to 6.5; b) separating and concentrating the organic layer obtained in step (a); c) dissolving the concentrate obtained in step (b) in a solvent selected from ethylacetate, methanol, ethanol, isopropyl alcohol, acetonitrile, dioxane and a mixture thereof; d) mixing tert-butylamine to the solution obtained in step (c ); and e) precipitating perindopril tert-butylamine salt from the solution obtained in step (d ).
  • An aqueous solution of impure perindopril or a perindopril salt can be prepared, for example, by dissolving perindopril or a perindopril salt such as perindopril tert-butylamine salt contaminated with known or unknown impurities in water or water mixed with any other solvent.
  • Perindopril or a salt thereof prepared in an aqueous media may also be used in step (a).
  • the pH of the solution is adjusted to 4.0 to 6.5, preferably to 4.5 to 6.0 with an acid such as hydrochloric acid or sulfuric acid or a base such as sodium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate or ammonia as required.
  • aqueous solution of perindopril is extracted with a solvent selected from methylenedichloride, which is preferable, chloroform, ethylenedichloride, toluene, heptane and a mixture thereof.
  • Precipitation in step (e) may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution or a combination thereof.
  • "Impure perindopril (or impure perindopril salt)" refers throught out the specification to perindopril (or perindopril salt) with total impurity content (by weight) of about 3.0% or above.
  • substantially pure perindopril tert-butylamine refers to perindopril tert- butylamine having chromatographic purity of not less than 97%, preferably not less than 99% and more preferably not less than 99.5%.
  • Perindopril salts such as tert-butyl amine salt produced by the prior art methods are contaminated with known and/or unknown impurities in significant amounts. The commonest among the impurities are:
  • Impure perindopril or an impure perindopril salt such as perindopril tert- butylamine salt is dissolved in water or water mixed with any other solvent.
  • "Impure perindopril (or impure perindopril salt)" refers to perindopril (or perindopril salt) with total impurity content (by weight) of about 3.0% or above.
  • An aqueous solution obtained' as a part of preparing perindopril or a salt thereof may also be used in the novel process for obtaining a substantially pure perindopril salt. The pH of the solution varies with the method of preparation, the salt used etc.
  • the pH of the solution is then adjusted to 4.0 to 6.5, preferably to 4.5 to 6.0 with an acid such as hydrochloric acid or sulfuric acid or a base such as sodium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate or ammonia as required.
  • the aqueous solution after pH adjustment is extracted with an organic solvent selected from methylenedichloride, chloroform, ethylenedichloride, toluene, heptane and a mixture thereof.
  • Perindopril is extracted into the organic phase and the impurities remain in the aqueous phase thereby effectively isolating perindopril from the impurities.
  • the aqueous solution of perindopril is preferably extracted with methylenedichloride.
  • the pH adjustment may also be done after mixing impure perindopril or its salt, the solvent for extraction and water.
  • the phases are separated and the organic layer is concentrated by distilling off the solvent.
  • the concentrate is dissolved in a solvent selected from ethylacetate, which is preferred, methanol, ethanol, isopropyl alcohol, acetonitrile, dioxane and a mixture thereof.
  • the solution is optionally filtered.
  • Tert-butylamine is added to the solution.
  • the amount of tert-butylamine to perindopril present in the solution is not critical but at least one mole of tert- butylamine per mole of perindopril is preferably used for good yield.
  • the contents may be heated.
  • Substantially pure perindpril tert-butylamine salt is precipitated from the solution.
  • the precipitation may be initiated by a commonly known method in the art such as cooling, seeding, partial removal of the solvent from the solution or a combination thereof.
  • Some or whole of the steps of the process may be repeated for obtaining perindopril tert-butylamine with desired purity, but by suitable choice of the conditions and solvents a single run may be enough for obtaining substantially pure perindopril tert-butylamine.
  • Substantially pure perindopril tert-butylamine refers to perindopril tert- butylamine having chromatographic purity of not less than 97%, preferably not less than 99% and more preferably not less than 99.5%.
  • Example 1 Perindopril tert-butylamine salt ( 15 gm, purity: 92.4%) is added to water (100 ml) and methylenedichloride (100 ml) and the pH of the mass is adjusted to 5.4 by using 20% dilute hydrochloric acid. The phases are separated and the aqueous layer is washed with methylenedichloride (2 x 75 ml). The methylenedichloride layer and washings are combined and the combined organic phase is washed with water (50 ml) and then with 10% aq.sodium chloride (50 ml). The organic layer is dried over sodium sulphate and concentrated to give a residue (99.3% purity).
  • Example 2 Ethylacetate (1800 ml) is added to (2S,3aS,7aS)- octahydro-1 H-indole-2- carboxylic acid benzyl ester (300 gm) at 25°C and stirred for 30 min. The reaction mass is cooled to 10°C, triethylamine (172.5 gm) is added and stirred for 5 minutes to form a clear solution. Hydroxybenzotriazole monohydrate (105 gm), dicyclohexylcarbodiimide (150 gm) are added to the reaction mass at 25°C under stirring.
  • Example 3 The mixture of (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid benzyl ester (300 gm, obtained in example 2), cyclohexane (750 ml), water (1050 ml) and 5% palladium-charcoal (60 gm) is taken in a hydrogenation flask and subjected to hydrogenation under a hydrogen pressure of 2 bars for 10 hours. The reaction mass is filtered over hiflo and washed with DM water (200 ml).
  • the layers are separated and the aqueous layer is washed with cyclohexane (900 ml) and the pH of the aqueous layer is adjusted to 5.7 by using aqueous ammonia. Then the aqueous layer is extracted with methylenedichloride (3000 ml), collected the organic layer and washed with water (500 ml).
  • reaction mass is stirred for 4 hour at 25°C, cooled to 0°C to 5°C and stirred for 2 hours at the same temperature.
  • the mass is filtered, washed the solid collected with ethyl acetate (100 ml) and dried at 50°C to give 180 gm of 99.8 % pure perindopril tert-butylamine salt.
  • Example 3 is repeated except that after hydrogenation, layer separation and washing the aqueous layer with cyclohexane, (2S,3aS,7aS)-1-[(2S)-2- [[(1S)-1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-1 H-indole-2- carboxylic acid is collected by freeze-drying.
  • Example 4 is repeated using the product thus obtained to give perindopril tert-butylamine with 95.5% purity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)

Abstract

On obtient du sel de tert-butylamine de perindopril en extrayant une solution aqueuse de périndopril ou son sel contaminé par des impuretés à l'aide d'un solvant organique approprié, tel que du dichlorure de méthylène avec un pH de 4.0 à 6.5, en séparant la couche organique, en isolant le périndopril de la couche organique et en le transformant en sel de tert-butylamine.
PCT/IN2003/000276 2003-08-21 2003-08-21 Procede de production de sel de tert-butylamine de perindopril pur Ceased WO2005019173A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000276 WO2005019173A1 (fr) 2003-08-21 2003-08-21 Procede de production de sel de tert-butylamine de perindopril pur
AU2003263584A AU2003263584A1 (en) 2003-08-21 2003-08-21 Process for pure perindopril tert-butylamine salt

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000276 WO2005019173A1 (fr) 2003-08-21 2003-08-21 Procede de production de sel de tert-butylamine de perindopril pur

Publications (1)

Publication Number Publication Date
WO2005019173A1 true WO2005019173A1 (fr) 2005-03-03

Family

ID=34204119

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000276 Ceased WO2005019173A1 (fr) 2003-08-21 2003-08-21 Procede de production de sel de tert-butylamine de perindopril pur

Country Status (2)

Country Link
AU (1) AU2003263584A1 (fr)
WO (1) WO2005019173A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG125976A1 (en) * 2005-03-11 2006-10-30 Servier Lab New gama crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it
SG125975A1 (en) * 2005-03-11 2006-10-30 Servier Lab New alpha crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it
WO2007017087A1 (fr) * 2005-07-25 2007-02-15 Lek Pharmaceuticals D.D. Procédé de préparation de périndopril cristallin
WO2007017893A3 (fr) * 2005-05-05 2007-05-10 Arch Pharmalabs Ltd Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate
JP2008115127A (ja) * 2006-11-07 2008-05-22 Permachem Asia Ltd ペリンドプリルの前駆体の製造方法、及びペリンドプリルの前駆体、並びにペリンドプリルエルブミンの製造方法と精製方法
WO2008125134A1 (fr) * 2007-04-13 2008-10-23 Helm Ag Procédé de préparation d'adsorbats de périndopril-tert-butylamine
US20150252001A1 (en) * 2012-10-10 2015-09-10 Piramal Enterprises Limited Process for preparation of perindopril intermediate
CN112047999A (zh) * 2020-09-18 2020-12-08 天津力生制药股份有限公司 一种γ晶型的精氨酸培哚普利盐的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083439A2 (fr) * 2000-07-06 2001-11-08 Les Laboratoires Serviers NOUVELLE FORME CRISTALLINE η DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL, SON PROCEDE DE PREPARATION, ET LES COMPOSITIONS PHARMACEUTIQUES QUI LA CONTIENNENT
EP1279665A2 (fr) * 2001-07-24 2003-01-29 Adir Un procédé pour la préparation de périndopril, leurs composés analogues et leurs sels en utilisant 2,5-dioxo-oxazolidines comme intermédiaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083439A2 (fr) * 2000-07-06 2001-11-08 Les Laboratoires Serviers NOUVELLE FORME CRISTALLINE η DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL, SON PROCEDE DE PREPARATION, ET LES COMPOSITIONS PHARMACEUTIQUES QUI LA CONTIENNENT
EP1279665A2 (fr) * 2001-07-24 2003-01-29 Adir Un procédé pour la préparation de périndopril, leurs composés analogues et leurs sels en utilisant 2,5-dioxo-oxazolidines comme intermédiaires

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG125976A1 (en) * 2005-03-11 2006-10-30 Servier Lab New gama crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it
SG125975A1 (en) * 2005-03-11 2006-10-30 Servier Lab New alpha crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it
WO2007017893A3 (fr) * 2005-05-05 2007-05-10 Arch Pharmalabs Ltd Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate
WO2007017087A1 (fr) * 2005-07-25 2007-02-15 Lek Pharmaceuticals D.D. Procédé de préparation de périndopril cristallin
JP2009502833A (ja) * 2005-07-25 2009-01-29 レツク・フアーマシユーテイカルズ・デー・デー 結晶形ペリンドプリルの製造方法
EA013018B1 (ru) * 2005-07-25 2010-02-26 Лек Фармасьютиклз Д. Д. Способ получения кристаллического периндоприла
US7923570B2 (en) 2005-07-25 2011-04-12 Lek Pharmaceuticals, D.D. Process for the preparation of crystalline perindopril
JP2008115127A (ja) * 2006-11-07 2008-05-22 Permachem Asia Ltd ペリンドプリルの前駆体の製造方法、及びペリンドプリルの前駆体、並びにペリンドプリルエルブミンの製造方法と精製方法
WO2008125134A1 (fr) * 2007-04-13 2008-10-23 Helm Ag Procédé de préparation d'adsorbats de périndopril-tert-butylamine
US20150252001A1 (en) * 2012-10-10 2015-09-10 Piramal Enterprises Limited Process for preparation of perindopril intermediate
CN112047999A (zh) * 2020-09-18 2020-12-08 天津力生制药股份有限公司 一种γ晶型的精氨酸培哚普利盐的制备方法
CN112047999B (zh) * 2020-09-18 2022-12-02 天津力生制药股份有限公司 一种γ晶型的精氨酸培哚普利盐的制备方法

Also Published As

Publication number Publication date
AU2003263584A1 (en) 2005-03-10

Similar Documents

Publication Publication Date Title
JP3939553B2 (ja) ペリンドプリル及びその薬学的に許容されうる塩の新規合成方法
US5936104A (en) Process for producing 1,2-epoxy-3-amino-4-phenylbutane derivatives
US20040198988A1 (en) Novel method for synthesis of (2s, 3as, 7as)-1-{(s)-alanyl}-octahydro-1h-indole-2-carboxylic acid derivatives and use for synthesis of perindopril
WO2005019173A1 (fr) Procede de production de sel de tert-butylamine de perindopril pur
EP1362864B1 (fr) Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables
JP2004520446A (ja) ロサルタンカリウムの結晶化方法
IL110969A (en) Process for purification-N-) S] -1 (- ethoxycarbonyl (-3- phenylpropyl) - - N (6-trifluoroacetyl [- L-lysyl-L-proline)
EP1713771B1 (fr) Procede pour la preparation d'une nouvelle forme cristalline de perindopril
KR100557512B1 (ko) 엔 - (1(에스) - 에톡시카르보닐 - 3 - 페닐프로필) - 엘 - 아라닐 -아미노산의 약리적으로 허용되는 염의 제조법
US20090076288A1 (en) Process for isolation of desired isomers of nebivolol intermediates
US7615571B2 (en) Process for manufacture of pure (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl]amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid and its tert. butyl amine salt
EP1753720B1 (fr) Procede de preparation de perindopril et de sels de celui-ci
JPWO1999005164A1 (ja) Ｎ−（１（ｓ）−エトキシカルボニル−３−フェニルプロピル）−ｌ−アラニル−アミノ酸の薬理的に許容される塩の製造法
EP1861367B1 (fr) Procede ameliore de purification du perindopril
EP1679072B1 (fr) Procédé de synthèse de dérivés de l'acide (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylique et application à la synthése du perindopril
EA007948B1 (ru) НОВЫЙ СПОСОБ СИНТЕЗА (2S,3aS,7aS )-ПЕРГИДРОИНДОЛ-2-КАРБОНОВОЙ КИСЛОТЫ И ЕЁ СЛОЖНЫХ ЭФИРОВ, А ТАКЖЕ ИХ ПРИМЕНЕНИЕ ДЛЯ СИНТЕЗА ПЕРИНДОПРИЛА
US20060178422A1 (en) Process for making (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid
KR100798560B1 (ko) 페린도프릴 및 이들의 약제학적 허용 염의 합성을 위한방법
EP1833788B1 (fr) Procédé de preparation de perindopril erbumine
WO2007020012A1 (fr) Procede de preparation de perindopril erbumine
US20080183011A1 (en) Process for preparation of perindopril erbumine in alpha crystalline form
EP1792896A1 (fr) Procédé pour la préparation de perindopril et de ses sels
JPH11100364A (ja) 高純度ｎ−保護基−ｓ−フェニルシステインの製造方法
HK1089187B (en) Novel method for the synthesis of perindopril and the pharmaceutically acceptable salts thereof

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1302/CHENP/2003

Country of ref document: IN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 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: A1

Designated state(s): GH GM KE LS MW MZ 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 IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP