+

WO2006003672A1 - Procede de preparation d'amlodipine pure - Google Patents

Procede de preparation d'amlodipine pure Download PDF

Info

Publication number
WO2006003672A1
WO2006003672A1 PCT/IN2004/000195 IN2004000195W WO2006003672A1 WO 2006003672 A1 WO2006003672 A1 WO 2006003672A1 IN 2004000195 W IN2004000195 W IN 2004000195W WO 2006003672 A1 WO2006003672 A1 WO 2006003672A1
Authority
WO
WIPO (PCT)
Prior art keywords
amlodipine
phthalimido
solvent
methyl
preparation
Prior art date
Application number
PCT/IN2004/000195
Other languages
English (en)
Inventor
Satyanarayana Chava
Gorantla Seeta Ramanjaneyulu
Konudula Babu Rao
Original Assignee
Matrix Laboratories 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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Priority to PCT/IN2004/000195 priority Critical patent/WO2006003672A1/fr
Publication of WO2006003672A1 publication Critical patent/WO2006003672A1/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
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 two 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to an improved process for the preparation of Amlodipine and its pharmaceutically acceptable salts via the effective purification of phthalimido Amlodipine.
  • Amlodipine an active pharmaceutical ingredient, useful for treating cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegic.
  • cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegic.
  • Particularly useful forms of Amlodipine salts in human medicine are maleate and benzenesulfonate (besylate).
  • European patent No 89,167 discloses the preparation of phthalimido Amlodipine and its conversion to Amlodipine, its different pharmaceutically acceptable salts.
  • Amlodipine maleate salt was disclosed as being preferred salt than other pharmaceutically acceptable acid addition salts.
  • European Patent No 244,944 discloses that the benzenesulphonate (besylate) salt of Amlodipine is the most preferred salt being its good formulation properties and also disclosed the process for the preparation of Amlodipine besylate by the reaction of Amlodipine base with benzene sulphonic acid in methanol.
  • European Patent No. 089,167 discloses the preparation of phthalimido
  • Amlodipine by the reaction of ethyl-4-[2-(phthalimido) ethoxy] acetoacetate with 2- chlorobenzaldehyde and methyl -3-amino crotonate in iso-propanol at reflux temperature for about 21 hrs followed by evaporation of iso-propanol, treating the residue with acetic acid overnight at room temperature affords the phthalimido Amlodipine which upon reaction with methyl amine in ethanol followed by removal of solvent affords Amlodipine which is directly converted to maleate salt in methanol. The purity of the obtained maleate salt and the Amlodipine was not disclosed.
  • PCT Publication No WO 02/53535 discloses the preparation of phthalimido Amlodipine by reaction of 4-[2-(phthalimido) ethoxy] acetoacetate with 2-chloro benzaldehyde in iso-propanol at temperature 35 0 C - 40 0 C in presence of piperidine as catalyst followed by acidification with acetic acid, cooling to O 0 C - 5 0 C, separation of the organic layer, evaporation of solvent and isolation of the intermediate ethyl-2-(2- chlorobenzylidene)-4-[2-(phthalimido)ethoxy] acetoacetate which upon reaction with methyl 3-aminocrotonate in iso-propanol followed by removal of solvent and treating with acetic acid overnight affords the phthalimido Amlodipine: Phthalimido Amlodipine prepared as above is reacted with aqueous methylamine followed by extraction with an organic solvent. Separation of organic layer followed by e
  • the main object of the present invention is to provide a process for the purification of phthalimido Amlodipine and its use for the preparation of Amlodipine and its pharmaceutically acceptable salts.
  • Another object of the invention is to provide a process for the preparation of
  • the precipitated and isolated Amlodipine base is identified by its characteristic X-ray diffraction pattern; IR spectrum, melting range and confirmed as polymorphic Form-I.
  • the Phthalimido Amlodipine used as starting material is prepared as follows.
  • 4-[2-(phthalimido) ethoxy] acetoacetate is reacted with 2-chloro benzaldehyde and molar excess equivalents of methyl 3-aminocrotonate, preferably 1.5 mole equivalents to 3.0 mole equivalents wrt to 4-[2-(phthalimido) ethoxy] acetoacetate in iso-propanol at temperature at 70 0 C to about 83 0 C for about 12 hrs to 24 hrs. After the completion of reaction, iso-propanol is distilled off under vacuum. The obtained residue is treated with acetic acid at room temperature for about 16 to 24 hrs crystallizes the crude phthalimido Amlodipine.
  • Phthalimido Amlodipine thus obtained is purified by dissolving it in 1 to 6 volumes and more preferably 1 to 3 volumes of the solvent(s), preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter if any.
  • the solvent(s) preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter if any.
  • second solvent(s) preferably a hydrocarbon like n-hexane, n-heptane, methyl cyclohexane, cyclohexane and n-pentane to the clear solution in lot wise over a period of 1 to 6hrs.
  • reaction mass for about 30 min to 3 hrs at temperature about 30 0 C to about 50 0 C 5 cooling and mixing the reaction mass to low temperature preferably to about 10 0 C to about 30 0 C for about lhr to about 5 hrs. Isolation and drying of the crystallized pure phthalimido Amlodipine.
  • the invention can be further illustrated by a few non-limiting examples.
  • Stage - 1 Preparation of Phthalimido amlodipine: 2-chlorobenzaldehyde (27 g) and methyl 3-amino crotonate (64.8 g) are added to the suspension of 4-[2-(Phthalimido) ethoxy] acetoacetate (60 g) in iso-propanol (300 ml). Temperature of the reaction mass is raised and maintained for 21 hrs at reflux temperature. Distilled off the solvent under vacuum at temperature below 75 0 C. Washed the residue with n-Hexane and again removed the low volatiles under vacuum to get residue. Acetic acid (300 ml) is added to the residue, mixed for 22 hrs at room temperature.
  • Phthaliimido amlodipine is filtered and washed the wet cake with acetic acid and n- Hexane.
  • the wet cake is again mixed with methanol (150 ml) at room temperature for about 30 min, filtered and dried at 55 0 C - 60 0 C till constant weight.
  • Dry wt of the phthalimido Amlodipine crude is 26 g (Yield: 31.7%).
  • Phthalimido amlodipine (25 g) prepared as above in stage- 1 is dissolved in MDC (50 ml) at 30 0 C - 35 0 C. Filtered the insoluble matter.
  • n-Hexane (50 ml) is ' added to the filtrate slowly over lhr at 30 0 C - 35 0 C and mixed for another 2hrs. Again n-Hexane (50 ml) is added over 1 hr at 30 0 C - 35 0 C and maintained for another 2hrs at 20 0 C - 25 0 C.
  • the precipitated product is filtered, washed the wet cake with n-Hexane and dried at 60 0 C - 65 0 C.
  • Phthalimido amlodipine 50 g prepared as above is suspended in ethanolic methylamine (600 ml) and maintained for 17 hrs at 28 0 C - 32 0 C.
  • the reaction mass is slowly poured into hot water (1200 ml) held at 50 0 C - 55 0 C over 45 min and mixed for about 1 hr at 50 0 C - 55 0 C.
  • Reaction mass is slowly cooled and maintained for about 1 hr at 20 0 C - 25 0 C.
  • the precipitated solid is filtered, washed the wet cake with water. Dried the product at 55 0 C - 60 0 C till constant weight.

Landscapes

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

Abstract

La présente invention concerne un procédé amélioré de préparation d'Amlodipine pure au moyen de la purification efficace de phtalimido Amlodipine (3-éthyl-5-méthyl -2-[(2-phthalimido éthoxy) méthyl]-4-(2-chlorophényl)-1,4-dihydro-6-méthyl-3,5-dicarboxylate).
PCT/IN2004/000195 2004-07-02 2004-07-02 Procede de preparation d'amlodipine pure WO2006003672A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000195 WO2006003672A1 (fr) 2004-07-02 2004-07-02 Procede de preparation d'amlodipine pure

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000195 WO2006003672A1 (fr) 2004-07-02 2004-07-02 Procede de preparation d'amlodipine pure

Publications (1)

Publication Number Publication Date
WO2006003672A1 true WO2006003672A1 (fr) 2006-01-12

Family

ID=35782504

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2004/000195 WO2006003672A1 (fr) 2004-07-02 2004-07-02 Procede de preparation d'amlodipine pure

Country Status (1)

Country Link
WO (1) WO2006003672A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096724A1 (fr) * 2006-02-21 2007-08-30 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré de synthèse du bésylate d'amlodipine
US7671208B2 (en) 2007-03-30 2010-03-02 Esteve Quimica, S.A. Acetone solvate of phthaloyl amlodipine
CN101367759B (zh) * 2008-10-06 2011-03-16 北京赛科药业有限责任公司 一种高纯度苯磺酸氨氯地平的合成方法
US7979778B2 (en) 2004-09-25 2011-07-12 Aware, Inc. CRC counter normalization
WO2011117876A1 (fr) 2010-03-26 2011-09-29 Fdc Limited Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
CN111948306A (zh) * 2020-07-27 2020-11-17 北京百奥药业有限责任公司 一种测定苯磺酸氨氯地平中基因毒性杂质的方法
CN113024446A (zh) * 2021-03-15 2021-06-25 福建海西新药创制有限公司 一种利用微反应装置制备苯磺酸氨氯地平中间体的方法
CN115536577A (zh) * 2022-11-09 2022-12-30 浙江昂利康制药股份有限公司 一种氨氯地平碱的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089167A2 (fr) * 1982-03-11 1983-09-21 Pfizer Limited Dihydropyridines comme agents anti-ischaémiques et antihypertensifs, procédé pour leur production et compositions pharmaceutiques les contenant
US20020143046A1 (en) * 2000-12-29 2002-10-03 Peters Theodorus H. A. Process for making amlodipine, derivatives therof, and precursors therefor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089167A2 (fr) * 1982-03-11 1983-09-21 Pfizer Limited Dihydropyridines comme agents anti-ischaémiques et antihypertensifs, procédé pour leur production et compositions pharmaceutiques les contenant
US20020143046A1 (en) * 2000-12-29 2002-10-03 Peters Theodorus H. A. Process for making amlodipine, derivatives therof, and precursors therefor

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7979778B2 (en) 2004-09-25 2011-07-12 Aware, Inc. CRC counter normalization
WO2007096724A1 (fr) * 2006-02-21 2007-08-30 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré de synthèse du bésylate d'amlodipine
US7671208B2 (en) 2007-03-30 2010-03-02 Esteve Quimica, S.A. Acetone solvate of phthaloyl amlodipine
CN101367759B (zh) * 2008-10-06 2011-03-16 北京赛科药业有限责任公司 一种高纯度苯磺酸氨氯地平的合成方法
WO2011117876A1 (fr) 2010-03-26 2011-09-29 Fdc Limited Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
CN111948306A (zh) * 2020-07-27 2020-11-17 北京百奥药业有限责任公司 一种测定苯磺酸氨氯地平中基因毒性杂质的方法
CN113024446A (zh) * 2021-03-15 2021-06-25 福建海西新药创制有限公司 一种利用微反应装置制备苯磺酸氨氯地平中间体的方法
CN113024446B (zh) * 2021-03-15 2022-08-05 福建海西新药创制有限公司 一种利用微反应装置制备苯磺酸氨氯地平中间体的方法
CN115536577A (zh) * 2022-11-09 2022-12-30 浙江昂利康制药股份有限公司 一种氨氯地平碱的制备方法
CN115536577B (zh) * 2022-11-09 2024-04-30 浙江昂利康制药股份有限公司 一种氨氯地平碱的制备方法

Similar Documents

Publication Publication Date Title
EP1799644B1 (fr) Sels de lercanidipine
EP0296316B1 (fr) Enantiomères de dihydro-1,4-pyridine
SK104598A3 (en) Process for the manufacture of dihydropyridine derivatives
HU194871B (en) Process for production of dihydropiridin-carbonils and medical preparatives containing them
US20100174085A1 (en) crystalline polymorphic forms of fexofenadine
KR20010093781A (ko) 아믈로디핀 합성을 위한 중간체, 이의 제조 방법 및 이의용도
US20080070789A1 (en) Process for making amlodipine, derivatives thereof, and precursors therefor
EP0599220B1 (fr) Procédé pour la préparation du benzènesulfonate d'amlodipine
US20190284197A1 (en) Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same
WO2006003672A1 (fr) Procede de preparation d'amlodipine pure
KR100488384B1 (ko) 신규한제조방법
CN100390145C (zh) 4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-羟基丁基]-α,α-二甲基苯乙酸和其盐酸盐的结晶形式
AU2001278094A1 (en) Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperindinyl]-1-hydroxybutyl]-alpha, alpha-dimethylbenzene acetic acid and its hydrochloride
US20060258705A1 (en) Process for making crystalline donepezil hydrochloride monohydrate
WO2011117876A1 (fr) Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
US20050288330A1 (en) Process for producing a polymorphic form of (1-Benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine hydrochloride (donepezil hydrochloride)
US7671208B2 (en) Acetone solvate of phthaloyl amlodipine
EP2072510A1 (fr) Forme cristalline d'azélastine
WO2005023769A1 (fr) Procede pour l'elaboration de sels d'amlodipine
US5347006A (en) Method of preparing a polymorph of terfenadine
WO2007110884A2 (fr) Procede de preparation de chlorhydrate de fexofenadine anhydre tres pur
RU2146672C1 (ru) Способ получения 3-этил-5-метил(±)2[2-аминоэтокси)-метил]-4-(2-хлорфенил)-1,4-дигидро- 6-метил-3,5-пиридиндикарбоксилат монобензолсульфоната
RU2142942C1 (ru) Способ получения монобензолсульфоната 3-этил-5-метилового эфира 2-[(2-аминоэтокси)метил]-4-(2-хлорфенил)-1,4-дигидро-6-метил-3,5-пиридинди карбоновой кислоты
AU2001100434A4 (en) Process for making amlodipine, derivatives thereof, and precursors therefore
WO2003101965A1 (fr) Deux formes dihydrate cristallin de benzenesulfonate d'amlodipine a purete elevee, leurs procedes de preparation et leur utilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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: A1

Designated state(s): 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 IT 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

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
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载