+

WO2005005384A1 - Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline - Google Patents

Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline Download PDF

Info

Publication number
WO2005005384A1
WO2005005384A1 PCT/TR2003/000062 TR0300062W WO2005005384A1 WO 2005005384 A1 WO2005005384 A1 WO 2005005384A1 TR 0300062 W TR0300062 W TR 0300062W WO 2005005384 A1 WO2005005384 A1 WO 2005005384A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
atorvastatin
atorvastatin calcium
calcium
preparation
Prior art date
Application number
PCT/TR2003/000062
Other languages
English (en)
Inventor
Kadir Dabak
Hulya Keskin
Original Assignee
Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S.
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 Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S. filed Critical Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S.
Priority to AU2003247327A priority Critical patent/AU2003247327A1/en
Priority to PCT/TR2003/000062 priority patent/WO2005005384A1/fr
Publication of WO2005005384A1 publication Critical patent/WO2005005384A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • Fig.l shows the formula of [R-(R*,R*)]-2-(4-fluoropheny ⁇ )- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H-pyrrole- 1 -tert-butylheptanoate .
  • Fig.2 shows the formula of [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl]- 1 H-pyrrole- 1 -heptanoic acid hemi calcium salt (Atorvastatin calcium).
  • Fig.3 demonstrates the X-Ray diffractogram of amorphous form of atorvastatin calcium wherein the horizantal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Atorvastatin calcium the substance known by the chemical name [R-(R*, R*)]-2-(4- fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- 1 H-pyrrole- 1 -heptanoic acid hemi calcium salt is a synthetic HMGA-CoA reductase inhibitor which is used for the treatment of hyperlipidemia and hypercholesterolemia.
  • Atorvastatin in the pharmaceutical compositions is usually prepared as its calcium salt since it enables atorvastatin to be conveniently formulated in the pharmaceutical formulations.
  • Atorvastatin calcium is the substance which is sparingly soluble in water, with pKa
  • the crystalline forms are less soluble than the amorphous form, which may cause problems in bioavailabilty of atorvastatin in the body. It is very important to ensure uniformity of the substance being employed in a pharmaceutical formulation.
  • (1) from the crystalline form of atorvastatin calcium which comprise: dissolving crystalline form of atorvastatin in a solvent and removing of solvent (US 6,087,511) or alternatively adding a non solvent and filtering the precipitated amorphous form (WO 97/03960, US 6,274,740, US 6,087,311, US 6,528,660).
  • a process for the preparation of the amorphous atorvastatin calcium and hydrates thus consist of: a) dissolving atorvastatin tert-butyl ester (Figure 1) in a solvent, b) adding an aqueous alkaline or alkaline earth metal hydroxide solution to the reaction mixture, c) removing of the solvent, d) adding water and a water non soluble solvent, e) adding an aqueous calcium salt solution to the reaction mixture, f) separation of the phases and removing of the solvent to obtain desired amorphous atorvastatin calcium and hydrates thereof.
  • the process disclosed herein gives amorphous form of atorvastatin calcium in a simple process without interconversion of any crystalline form. Additional solvents are not necessary to precipitate amorphous form. Additionally to these, the problem of removal of water from the product is not observed.
  • atorvastatin tert-butyl ester (Fig.l) was dissolved in 100 ml of methanol, and a solution of 0.390 g of NaOH / 15 ml of water was added. Reaction mixture was stirred for 1 h at 50°C. After 1 h, TLC showed no starting material (TLC was performed on silica plate, eluent: Hexane/ethyl acetate: 1/1). Methanol was removed under reduced pressure. 100 ml of water and 100 ml of ethyl acetate were added. A solution of 0.870 g of Ca(CH 3 COO) . X H 2 O / 20 ml of water was added.
  • Reaction mixture was stirred for 1 h at 50°C. Mixture was cooled to room temperature and the phases were seperated. The organic phase was washed with 2X50 ml of water. The organic phase was concentrated under vacuo at 50 °C to give desired amorphous atorvastatin calcium.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de sel d'atorvastatine calcique (2:1) à partir d'ester tert-butylique d'atorvastatine (figure 1). Ce procédé consiste à (a) dissoudre l'ester tert-butylique d'atorvastatine (figure 1) dans un solvant, (b) ajouter une solution d'hydroxyde métallique alcalino-terreux ou alcaline aqueuse, (c) éliminer le solvant, d) ajouter de l'eau et un solvant non soluble dans l'eau, e) ajouter une solution aqueuse de sel de calcium, f) séparer les phases et éliminer le solvant de façon à obtenir l'atorvastatine calcique amorphe désirée et des hydrates de celle-ci. Ce procédé permet d'obtenir directement une forme amorphe sans interconversion d'une forme cristalline en une forme amorphe.
PCT/TR2003/000062 2003-07-15 2003-07-15 Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline WO2005005384A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003247327A AU2003247327A1 (en) 2003-07-15 2003-07-15 Process for the preparation of amortphous atorvastatin calcium without interconversion of any crystalline form
PCT/TR2003/000062 WO2005005384A1 (fr) 2003-07-15 2003-07-15 Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2003/000062 WO2005005384A1 (fr) 2003-07-15 2003-07-15 Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline

Publications (1)

Publication Number Publication Date
WO2005005384A1 true WO2005005384A1 (fr) 2005-01-20

Family

ID=34057109

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2003/000062 WO2005005384A1 (fr) 2003-07-15 2003-07-15 Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline

Country Status (2)

Country Link
AU (1) AU2003247327A1 (fr)
WO (1) WO2005005384A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006011155A1 (fr) * 2004-07-26 2006-02-02 Apollo International Limited Procede en enceinte unique pour calcium d'atorvastatine amorphe
US20060106230A1 (en) * 2004-10-18 2006-05-18 Michael Pinchasov Processes for preparing amorphous atorvastatin hemi-calcium
US7511140B2 (en) 2002-08-13 2009-03-31 Astrazeneca Ab Process for preparing the calcium salt of rosuvastatin
US8063213B2 (en) 2003-06-05 2011-11-22 Astrazeneca Uk Limited Production of rosuvastatin calcium salt
US9371291B2 (en) 2003-10-24 2016-06-21 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin
WO2002083637A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin
WO2002083637A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAUMANN K L ET AL: "THE CONVERGENT SYNTHESIS OF CI-981, AN OPTICALLY ACTIVE, HIGHLY POTENT, TISSUE SELECTIVE INHIBITOR OF HMG-COA REDUCTASE", 21 April 1992, TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, PAGE(S) 2283-2284, ISSN: 0040-4039, XP000608147 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7511140B2 (en) 2002-08-13 2009-03-31 Astrazeneca Ab Process for preparing the calcium salt of rosuvastatin
US7842807B2 (en) 2002-08-13 2010-11-30 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
US8063213B2 (en) 2003-06-05 2011-11-22 Astrazeneca Uk Limited Production of rosuvastatin calcium salt
US9371291B2 (en) 2003-10-24 2016-06-21 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof
WO2006011155A1 (fr) * 2004-07-26 2006-02-02 Apollo International Limited Procede en enceinte unique pour calcium d'atorvastatine amorphe
US20060106230A1 (en) * 2004-10-18 2006-05-18 Michael Pinchasov Processes for preparing amorphous atorvastatin hemi-calcium

Also Published As

Publication number Publication date
AU2003247327A1 (en) 2005-01-28

Similar Documents

Publication Publication Date Title
EP1185264B1 (fr) Procede pour la preparation d'atorvastatine calcique amorphe
EP1345896B1 (fr) Formes cristallines d'atorvastatine
AU2002255479B2 (en) Crystalline forms VI and VII of atorvastatin clacium
PL191017B1 (pl) Sposób otrzymywania bezpostaciowej atorwastatyny
WO2002057228A1 (fr) Atorvastatine calcique
US20050119493A1 (en) Process for the preparation of amorphous atorvastin calcium salt (2:1)
MX2011006624A (es) Procedimiento de preparacion de esteres activados.
WO2005005384A1 (fr) Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline
CA2676443C (fr) Solvates atorvastatine calcique propylene glycol
WO2008075165A1 (fr) Nouveau procédé pour la synthèse de l'acide [r-(r*, r*)]-2-(4-fluorophényl)-bêta, delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1h-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci
WO2007096751A1 (fr) Procédé de préparation d'atorvastatine calcique
ZA200602222B (en) Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl]-1 H-pyrrole-1H-pyrrole-1-heptanoic acid
CA2578722C (fr) Processus pour calcium d'atorvastatine amorphe
WO2005090301B1 (fr) Forme cristalline d'hemi-calcium d'atorvastatine
EP1732886B1 (fr) Polymorphes d'ester de tert-butyle d'atorvastatine et leur utilisation en tant qu'intermediaires dans la preparation d'atorvastatine
US7361772B2 (en) Process for the production of atorvastatin calcium
EP1853558A1 (fr) Procédé de fabrication d hémicalcium d atorvastatine
EP1963263A1 (fr) Polymorphes d'un sel de magnesium (2:1) de l'acide [r-(r*, r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lh-pyrrole-l-heptanoique
WO2006048894A1 (fr) Nouvelles formes cristallines de calcium d'atorvastatine et procedes de fabrication
WO2014041059A1 (fr) Procédé de production d'intermédiaires de l'atorvastatine
WO2012015157A1 (fr) Nouvelle forme cristalline du sel d'hémicalcium de l'atorvastatine, son hydrate et son procédé de production
CA2567931A1 (fr) Formes salines d'atorvastatine
KR20100062601A (ko) 무정형 아토르바스타틴 칼슘염의 제조방법
WO2005033078A1 (fr) Procede de production d'atorvastatine calcique
US20050165242A1 (en) Process for the preparation of amorphous atorvastatin calcium

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 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 NO NZ OM PH PL PT RO RU SC SD SE SG SK SL 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

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