EP1294712A1 - Procede de cristallisation du losartan potassium - Google Patents

Procede de cristallisation du losartan potassium

Info

Publication number
EP1294712A1
EP1294712A1 EP01274254A EP01274254A EP1294712A1 EP 1294712 A1 EP1294712 A1 EP 1294712A1 EP 01274254 A EP01274254 A EP 01274254A EP 01274254 A EP01274254 A EP 01274254A EP 1294712 A1 EP1294712 A1 EP 1294712A1
Authority
EP
European Patent Office
Prior art keywords
losartan
potassium
losartan potassium
acetone
solvent
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.)
Withdrawn
Application number
EP01274254A
Other languages
German (de)
English (en)
Inventor
Aurobindo Pharma Ltd RAMASHANKAR
Vennapu Aurobindo Pharma Limited REDDY RAVINDER
Meenakshisunderam Sivakumaran
Vijay Kumar Aurobindo Pharma Limited HANDA
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.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma 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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of EP1294712A1 publication Critical patent/EP1294712A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a c-rystallization process to obtain losartan Potassium
  • Losartan Potassium is also known as 2-n-butyl-4-chloro-5-hydroxymethyl-1- [ [2'- (2H-tetrazole-5-yl) biphenyl-4-yi] methyl] imidazole potassium salt and is useful in the treatment of hypertension.
  • Losartan is known to inhibit the action of octapeptide hormone angiotensin II and Is useful therefore in alleviating angiotensin induced hypertension. Further, it has been reported that losartan when administered with a diuretic such as furosemide or hydrochlorot ⁇ iazide exhibits an enhanced anti-hypertensive effect. Administration of losartan with a non-steroidal anti- inflammatory drug can prevent renal failure.
  • Losartan is known to exhibit polymorphphism (Ref: US Patent 5,608,075).
  • Two polymorphic forms of Losartan Potassium, Form I and Form II have been reported in US Patent 5,608,075 alongwith their methods of preparation. Characterization of these two polymorphic forms has been described through applications of X-ray powder diffraction pattern, DSC thermograms, FTIR spectra, Raman spectra and solid state 13 C NMR.
  • Polymo ⁇ h Form I has been prepared in US Patent 5,608,075 by adding an aqueous solution of Losartan Potassium to a refluxing mixture of isopropanol/cyclohexene and removing water by distilling cyclohexe ⁇ e isopropanol/water ternary azeotrope at 64° C. Losartan Potassium Form I crystallizes out at 69° C.
  • Losartan Potassium has been achieved from a mixture of isopiopanol and cyclohexene and this crystalline material has been characterized as polymo ⁇ h Form I.
  • Crystallization process described in WO 98/18787 requires adequate precision to consistently obtain po'ymo ⁇ h Form I and mixture of solvents, cyclohexene and isopropanol is difficult to separate.
  • the inventors have su ⁇ risingly discovered that Losartan Potassium polymo ⁇ h Form I can be prepared in one pot by reacting triphenylmethyl protected Losartan with Potassium hydroxide in methanoi/acetone without isolating the free Losartan acid and requires no seeding.
  • This invention relates to the process to manufacture Losartan Potassium Form I without use of isopropanol/cyclohexene solvent mixture.
  • Losartan free acid is suspended in a solvent and potassium hydroxide is added to obtain a clear solution, which is then concentrated under reduced pressure to remove most of the solvent.
  • An anti-solvent is added to crystallize Losartan Potassium.
  • the solvents to prepare Losartan Potassium include methanol, ethanol, butanol but preferably the salt formation is carried out in methanol.
  • Anti-solvent is selected from common solvents such ethyl acetate, acetonitrile, toluene and acetone but the preferred anti-solvent is acetone.
  • Losartan free acid or triphenylmethyl protected Losartan may be prepared using the reactions and techniques described in US Patent 5,138,069 and WO 93/10106.
  • Trityl Losartan 2-n-buty -chloro-5-hydroxymethyl-1- [ [2'- [ (2-triphenylmethyl) tetrazole-5-yl] biphenyl-4-yl] methyl] imidazole (herein referred as Trityl Losartan), a key intermediate
  • Losartan Potassium hydroxide in an alcohol, preferably methanol, to perform deprotection and generate in situ Losartan Potassium which is then isolated in dessred polymo ⁇ h Form I by distilling methanol and adding an anti-solvent such as acetonitrile, toluene, ethyl acetate and preferably acetone. Both the reaction and the crystallization may be effected in the same reaction vessel, and no expensive separation techniques, such as extraction or isolation of Losartan free acid are necessary. Such a process of obtaining Losartan Potassium polymo ⁇ h Form I directly from Trityl losartan is not reported hitherto in literature and hence constitutes an object of the present invention.
  • the described preparation is done essentially under anhydrous condition and thus avoids elaborate azeotropic distillation for water removal.
  • the desired polymo ⁇ h Form I Losartan Potassium is obtained directly, that is, without having to isolate the free Losartan acid, which results in increased efficiency and contributes to the lower production cost.
  • trityl losartan is dissolved in 6-8 times by volume in methanol and equimolar quantity of potassium hydroxide is added. The resulting mixture is refluxed for a few hours till disappearance of trityl losartan is observed.
  • Tritanol is recovered by filtration and methanol is distilled under reduced pressure. Acetone is added to the residue and distillation is continued to remove last traces of methanol.
  • Losartan Potassium is obtained as a free flowing slurry in acetone that is ffiilltteerreedd aanndd ddrriieedd..
  • TThhee ddiiffffeerreennttiiaall ssccaannnniinngg ccaalloorudimetric analysis and X-ray powder diffraction pattern confirm this to be polymo ⁇ hic modification I
  • Residue was diluted with 25 ml. acetone and contents cooled to 20-25° C for 10 min and product filtered under nitrogen atmosphere and washed with 5 ml. acetone. Product was dried 55-60° C under reduced pressure to yield 4.88 g. (89.5% of theory) Losartan Potassium Form I (DSC, XRPD).
  • Losartan Potassium Form I was prepared from Losartan acid in methanol as described in Example 2 and ethyl acetate was used in place of acetone. Yield: 4.95 g. (91% of theory).
  • Losartan Potassium Form I was prepared from Losartan acid following the procedure described in Example 2 and acetonitrile was added as anti-solvent to isolate the product. Yield: 4.8 g. (88% of theory).
  • Example 6
  • Losartan Potassium was prepared by reacting Losartan acid in n-butanol with potassium hydroxide as described in Example 6 and the product was isolated as polymo ⁇ h Form I by addition of ethyl acetate as anti-solvent in place of acetone. Yield: 4.85 g. (89% of theory).
  • Losartan Potassium was prepared in n-butanol as given in Example 6 and Form I of Losartan Potassium was isolated with toluene. Yield: 4.9 g. (90% of theory).
  • Losartan Potassium was prepared in n-butanol as described in Example 6 and Form I was obtained by adding acetonitrile. Yield: 4.8 g. (88% of theory).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de la forme cristalline (I) du Losartan Potassium. Ce procédé consiste i) à faire réagir le composé de formule (I), dans lequel 'R' représente un groupe protecteur d'hydrogène ou de triphénylméthyle (trityl) avec de l'hydroxyde de potassium dans un alcool, ii) à effectuer une concentration sous une pression réduite afin d'éliminer l'alcool, et iii) à ajouter un anti-solvant pour isoler le Losartan Potassium.
EP01274254A 2001-05-18 2001-11-20 Procede de cristallisation du losartan potassium Withdrawn EP1294712A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
INMA00001403 2001-05-18
IN403CH2001 2001-05-18
PCT/IN2001/000205 WO2002094816A1 (fr) 2001-05-18 2001-11-20 Procede de cristallisation du losartan potassium

Publications (1)

Publication Number Publication Date
EP1294712A1 true EP1294712A1 (fr) 2003-03-26

Family

ID=11097003

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01274254A Withdrawn EP1294712A1 (fr) 2001-05-18 2001-11-20 Procede de cristallisation du losartan potassium

Country Status (6)

Country Link
EP (1) EP1294712A1 (fr)
JP (1) JP2004520446A (fr)
BG (1) BG107478A (fr)
SI (1) SI21236A (fr)
SK (1) SK722003A3 (fr)
WO (1) WO2002094816A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030135041A1 (en) 2002-01-04 2003-07-17 Orchid Chemicals & Pharmaceuticals Limited, India Synthesis of ceftiofur intermediate
US20060241305A1 (en) * 2002-10-31 2006-10-26 Yatendra Kumar Amorphous form of losartan potassium
ITMI20030328A1 (it) * 2003-02-25 2004-08-26 Dinamite Dipharma S P A In Forma A Bbreviata Diph Polimorfi di losartan potassio e procedimento per la loro preparazione.
WO2004076442A1 (fr) * 2003-02-28 2004-09-10 Ranbaxy Laboratories Limited Polymorphes de losartan
EP1608641A1 (fr) * 2003-04-03 2005-12-28 IPCA Laboratories Limited Procede de synthese de losartan potassique
US7345071B2 (en) 2003-05-07 2008-03-18 Ipca Laboratories Limited Process for the synthesis of Losartan potassium
PT1658281E (pt) * 2003-08-27 2010-10-12 K S Zentiva Método de remoção do grupo protector trifenilmetano
ITMI20032472A1 (it) * 2003-12-16 2005-06-17 Dinamite Dipharma S P A In Forma A Bbreviata Diph Procedimento per la preparazione di losartan potassio cristallino
WO2005066158A2 (fr) * 2004-01-06 2005-07-21 Ipca Laboratories Limited Procede ameliore de synthese du losartan potassique
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
EP1729766A1 (fr) * 2004-03-01 2006-12-13 LEK Pharmaceuticals D.D. Formulation pharmaceutique
US20050250827A1 (en) * 2004-05-05 2005-11-10 Etinger Marina Y Preparation of candesartan cilexetil in high purity
WO2010046804A2 (fr) * 2008-10-21 2010-04-29 Alembic Limited Procédé de préparation du losartan potassium forme i

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
AU665388B2 (en) * 1991-11-18 1996-01-04 E.I. Du Pont De Nemours And Company Tetrazolylphenylboronic acid intermediates for the synthesis of AII receptor antagonists
PT937068E (pt) * 1996-10-29 2002-07-31 Merck & Co Inc Processo para a cristalizacao de losartan
HU222773B1 (hu) * 2000-04-21 2003-10-28 Richter Gedeon Vegyészeti Gyár Rt. Eljárás egy ismert tetrazolszármazék előállítására

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02094816A1 *

Also Published As

Publication number Publication date
BG107478A (bg) 2004-01-30
WO2002094816A1 (fr) 2002-11-28
JP2004520446A (ja) 2004-07-08
SK722003A3 (en) 2003-12-02
SI21236A (sl) 2003-12-31

Similar Documents

Publication Publication Date Title
JP6514398B2 (ja) メチル｛４，６−ジアミノ−２−［１−（２−フルオロベンジル）−１Ｈ−ピラゾロ［３，４−ｂ］ピリジン−３−イル］ピリミジン−５−イル｝メチルカルバメートの調製方法および医薬上活性な化合物として用いるためのその精製方法
US8592474B2 (en) Process for the preparation or purification of olmesartan medoxomil
JP5535082B2 (ja) ボセンタン、その多形形態及びその塩の合成方法
WO2002094816A1 (fr) Procede de cristallisation du losartan potassium
EP3433233B1 (fr) Nouvelle forme cristalline de sel de 1-(5-(2,4-difluorophényl)-1-((3-fluorophényl)sulfonyl)-4-méthoxy-1h-pyrrol-3-yl)-n-méthylméthanamine
EP1274702B1 (fr) Procede de synthese d'un derive connu du tetrazol
WO2018008219A1 (fr) Intermédiaire d'azilsartan, azilsartan, procédé de production d'un intermédiaire d'azilsartan et procédé de production d'azilsartan
JP2004520446A5 (fr)
WO2017131218A1 (fr) Azilsartan et son procédé de production
EP1789412B1 (fr) Base d'alfuzosine cristalline
EP1912956B1 (fr) Sels métalliques du 2'-(1h-tetrazol-5-yl)-1,1'-biphényl-4-carboxaldéhyde
EP2016073B1 (fr) Procede de preparation d'irbesartan pur
US6916935B2 (en) Losartan potassium synthesis
US7345071B2 (en) Process for the synthesis of Losartan potassium
CZ2012274A3 (cs) Zpusob prípravy vysoce cisté draselné soli azilsartanu medoxomilu
EP2022790A1 (fr) Procédé pour la préparation ou la purification d'olmésartan médoxomil
US20230089434A1 (en) Synthesis of nirogacestat
CN117858866A (zh) 用于制备色胺衍生物的方法
WO2005066158A2 (fr) Procede ameliore de synthese du losartan potassique
JP2010077070A (ja) イミダゾール誘導体の精製方法
EP1608641A1 (fr) Procede de synthese de losartan potassique

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030117

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20030828

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050816