WO2002094816A1 - Process for the crystallization of losartan potassium - Google Patents
Process for the crystallization of losartan potassium Download PDFInfo
- Publication number
- WO2002094816A1 WO2002094816A1 PCT/IN2001/000205 IN0100205W WO02094816A1 WO 2002094816 A1 WO2002094816 A1 WO 2002094816A1 IN 0100205 W IN0100205 W IN 0100205W WO 02094816 A1 WO02094816 A1 WO 02094816A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- losartan
- potassium
- losartan potassium
- acetone
- solvent
- Prior art date
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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
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01274254A EP1294712A1 (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
JP2002591489A JP2004520446A (en) | 2001-05-18 | 2001-11-20 | Crystallization method of losartan potassium |
SI200120042A SI21236A (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
SK72-2003A SK722003A3 (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
BG107478A BG107478A (en) | 2001-05-18 | 2003-01-17 | Process for the crystallization of losartan potassium |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN403/MAS/2001 | 2001-05-18 | ||
IN403CH2001 | 2001-05-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002094816A1 true WO2002094816A1 (en) | 2002-11-28 |
Family
ID=11097003
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2001/000205 WO2002094816A1 (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1294712A1 (en) |
JP (1) | JP2004520446A (en) |
BG (1) | BG107478A (en) |
SI (1) | SI21236A (en) |
SK (1) | SK722003A3 (en) |
WO (1) | WO2002094816A1 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004039352A2 (en) * | 2002-10-31 | 2004-05-13 | Ranbaxy Laboratories Limited | Amorphous form of losartan potassium |
WO2004076442A1 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Polymorphs of losartan |
WO2004076406A2 (en) * | 2003-02-25 | 2004-09-10 | Dipharma S.P.A. | Losartan potassium polymorphs and process for the preparation thereof |
US6803461B2 (en) | 2002-01-04 | 2004-10-12 | Orchid Chemicals And Pharmaceuticals Limited | Synthesis of ceftiofur intermediate |
WO2004087691A1 (en) * | 2003-04-03 | 2004-10-14 | Ipca Laboratories Limited | A process for the synthesis of losartan potassium |
WO2005021535A2 (en) * | 2003-08-27 | 2005-03-10 | Zentiva, A.S. | A method of removing the triphenylmethane protecting group |
EP1544198A1 (en) * | 2003-12-16 | 2005-06-22 | Dipharma S.p.A. | A process for the preparation of crystalline losartan potassium |
WO2005066158A2 (en) * | 2004-01-06 | 2005-07-21 | Ipca Laboratories Limited | An improved process for the synthesis of losartan potassium |
WO2005084670A1 (en) * | 2004-03-01 | 2005-09-15 | Lek Pharmaceuticals D.D. | Pharmaceutical formulation |
US7345071B2 (en) | 2003-05-07 | 2008-03-18 | Ipca Laboratories Limited | Process for the synthesis of Losartan potassium |
US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
WO2010046804A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for preparation of losartan potassium form i |
JP2010116409A (en) * | 2004-05-05 | 2010-05-27 | Teva Pharmaceutical Industries Ltd | Preparation of candesartan cilexetil in high purity |
Citations (4)
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 |
WO1993010106A1 (en) * | 1991-11-18 | 1993-05-27 | E.I. Du Pont De Nemours And Company | Tetrazolylphenylboronic acid intermediates for the synthesis of aii receptor antagonists |
WO1998018787A1 (en) * | 1996-10-29 | 1998-05-07 | Merck & Co., Inc. | Process for the crystallization of losartan |
WO2001081336A1 (en) * | 2000-04-21 | 2001-11-01 | Richter Gedeon Vegyészeti Gyár Rt. | Process for the synthesis of a known tetrazol derivative |
-
2001
- 2001-11-20 SK SK72-2003A patent/SK722003A3/en unknown
- 2001-11-20 SI SI200120042A patent/SI21236A/en not_active IP Right Cessation
- 2001-11-20 JP JP2002591489A patent/JP2004520446A/en active Pending
- 2001-11-20 EP EP01274254A patent/EP1294712A1/en not_active Withdrawn
- 2001-11-20 WO PCT/IN2001/000205 patent/WO2002094816A1/en not_active Application Discontinuation
-
2003
- 2003-01-17 BG BG107478A patent/BG107478A/en unknown
Patent Citations (4)
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 |
WO1993010106A1 (en) * | 1991-11-18 | 1993-05-27 | E.I. Du Pont De Nemours And Company | Tetrazolylphenylboronic acid intermediates for the synthesis of aii receptor antagonists |
WO1998018787A1 (en) * | 1996-10-29 | 1998-05-07 | Merck & Co., Inc. | Process for the crystallization of losartan |
WO2001081336A1 (en) * | 2000-04-21 | 2001-11-01 | Richter Gedeon Vegyészeti Gyár Rt. | Process for the synthesis of a known tetrazol derivative |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6803461B2 (en) | 2002-01-04 | 2004-10-12 | Orchid Chemicals And Pharmaceuticals Limited | Synthesis of ceftiofur intermediate |
WO2004039352A2 (en) * | 2002-10-31 | 2004-05-13 | Ranbaxy Laboratories Limited | Amorphous form of losartan potassium |
WO2004039352A3 (en) * | 2002-10-31 | 2004-09-02 | Ranbaxy Lab Ltd | Amorphous form of losartan potassium |
WO2004076406A2 (en) * | 2003-02-25 | 2004-09-10 | Dipharma S.P.A. | Losartan potassium polymorphs and process for the preparation thereof |
WO2004076406A3 (en) * | 2003-02-25 | 2005-01-13 | Dipharma Spa | Losartan potassium polymorphs and process for the preparation thereof |
WO2004076442A1 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Polymorphs of losartan |
WO2004087691A1 (en) * | 2003-04-03 | 2004-10-14 | Ipca Laboratories Limited | A process for the synthesis of losartan potassium |
US7345071B2 (en) | 2003-05-07 | 2008-03-18 | Ipca Laboratories Limited | Process for the synthesis of Losartan potassium |
WO2005021535A3 (en) * | 2003-08-27 | 2005-06-09 | Zentiva As | A method of removing the triphenylmethane protecting group |
WO2005021535A2 (en) * | 2003-08-27 | 2005-03-10 | Zentiva, A.S. | A method of removing the triphenylmethane protecting group |
EA011507B1 (en) * | 2003-08-27 | 2009-04-28 | Зентива А.С. | A method for the preparation potassium salts of losartan |
EP1544198A1 (en) * | 2003-12-16 | 2005-06-22 | Dipharma S.p.A. | A process for the preparation of crystalline losartan potassium |
WO2005066158A2 (en) * | 2004-01-06 | 2005-07-21 | Ipca Laboratories Limited | An improved process for the synthesis of losartan potassium |
WO2005066158A3 (en) * | 2004-01-06 | 2005-08-25 | Ipca Lab Ltd | An improved process for the synthesis of losartan potassium |
US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
WO2005084670A1 (en) * | 2004-03-01 | 2005-09-15 | Lek Pharmaceuticals D.D. | Pharmaceutical formulation |
JP2010116409A (en) * | 2004-05-05 | 2010-05-27 | Teva Pharmaceutical Industries Ltd | Preparation of candesartan cilexetil in high purity |
WO2010046804A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for preparation of losartan potassium form i |
WO2010046804A3 (en) * | 2008-10-21 | 2010-11-04 | Alembic Limited | A process for preparation of losartan potassium form i |
Also Published As
Publication number | Publication date |
---|---|
SK722003A3 (en) | 2003-12-02 |
EP1294712A1 (en) | 2003-03-26 |
SI21236A (en) | 2003-12-31 |
BG107478A (en) | 2004-01-30 |
JP2004520446A (en) | 2004-07-08 |
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