EP1294712A1 - Process for the crystallization of losartan potassium - Google Patents

Process for the crystallization of losartan potassium

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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Withdrawn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)
French (fr)
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/en
Withdrawn legal-status Critical Current

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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).

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

Abstract

There is disclosed a process to prepare crystalline Form (I) of Losartan Potassium which comprises: i) Reacting compound of formula (I). Where 'R' represents hydrogen or triphenylmethyl (trityl) protecting group with potassium hydroxide in an alcohol, and ii) Concentration under reduced pressure to remove alcohol, and iii) Adding an anti-solvent to isolate Losartan Potassium.

Description

PROCESS FOR THE CRYSTALLIZATION OF LOSARTAN POTASSIUM
Field of the Invention:
This invention relates to a c-rystallization process to obtain losartan Potassium
Form I. Losartan is used in the treatment of hypertension. Background of the Invention and Prior Art and Drawbacks:
This invention relates to crystallization process to prepare Losartan Potassium Form I. 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 hydrochlorotπiazide 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 13C NMR.
Polymoφh 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 cyclohexeπe isopropanol/water ternary azeotrope at 64° C. Losartan Potassium Form I crystallizes out at 69° C.
In WO 98/18787, a process to prepare polymorph Form I has been disclosed wherein solution of potassium salt in aqueous isopropanol is heated to lower the water content to about 2.6% by removing isopropanol/water mixture, immense seeding with Losartan Potassium slurry in cyclohexene is done until the seed remains undissolved and removing water to 0.02-0.11% by distilling out the ternary azeotrope while simultaneously adding cyclohexene The crystallized material 5s recovered by filtration.
In both these disclosed processes, crystalline Losartan Potassium has been achieved from a mixture of isopiopanol and cyclohexene and this crystalline material has been characterized as polymoφh Form I. Crystallization process described in WO 98/18787 requires adequate precision to consistently obtain po'ymoφh Form I and mixture of solvents, cyclohexene and isopropanol is difficult to separate. The inventors have suφrisingly discovered that Losartan Potassium polymoφh 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.
Detailed Description of the Invention:
This invention relates to the process to manufacture Losartan Potassium Form I without use of isopropanol/cyclohexene solvent mixture. Typically 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.
Alternatively, 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
in the manufacture of Losartan is refluxed with Potassium hydroxide in an alcohol, preferably methanol, to perform deprotection and generate in situ Losartan Potassium which is then isolated in dessred polymoφh 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 polymoφh Form I directly from Trityl losartan is not reported hitherto in literature and hence constitutes an object of the present invention. Additionally, the described preparation is done essentially under anhydrous condition and thus avoids elaborate azeotropic distillation for water removal. The desired polymoφh 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.
Typically, 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 ccaallooririimetric analysis and X-ray powder diffraction pattern confirm this to be polymoφhic modification I
The following examples further illustrate the preparation of Losartan Potassium polymoφh form I and are not to be construed as any limitation thereof.
Example 1
100 gm. (0.152 mol.) 2-n-butyl-4-chloro-5-hydroxymethyl-1- [ [2 - [ (2-triphenylmethyl) tetrazole-5-yl] biphenyl-4-yl] methyl] imidazole (Trityl Losartan) was suspended in 650 ml. methanol. 10 gm. of 85% potassium hydroxide (0.152 mol.) was added and the mixture was refluxed under nitrogen atmosphere for nearly 6 hours. The reaction mass was cooled to 8-10° C and tritanol byproduct was removed by filtration and washed with 50 ml. chilled methanol. The filtrate was treated with 1 g. charcoal and filtered through celite. Methanol solution was then concentrated at 45-50° C to remove most of methanol. 200 ml. acetone was added and distillation continued under reduced pressure to reduce the volume to approximately 120 ml. The white crystalline slurry was cooled to room temperature, filtered and product washed with 50 ml. acetone and dried in vacuum oven to obtain Losartan Potassium. Yield: 60 g. (86.58% of theory). DSC analysis (Figure 1) and X-ray powdered diffraction pattern (Figure 2) comply with that reported for polymoφh Form I.
Example 2
To a suspension of 5 gm. (11.82 m. mol.) 2-n-buty -chloro-5-hydroxymethyl-1- [ [2'- [ (2H- tetrazole-5-yl] biphenyl-4-yl] methyl] imidazole (Losartan acid) in 25 ml. methanol, 0.75 g. (86%) (11.52 m. mol.) potassium hydroxide powder was added and mass stirred at ambient temperature to obtain an almost clear solution. This was filtered through celite and the clarified solution was concentrated to remove most of methanol at 45-50° C under reduced pressure. 25 ml. of acetone was added and distillation continued to distil most of the methanol/acetone mixture. 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).
Example 3
To a suspension of 5 gm. (11.82 m. mol.) of Losartan acid in 25 ml. dry ethanol was added 0.75 g. (86%) (11.52 m. mol.) potassium hydroxide powder and mass stirred at ambient temperature for 25 minutes to obtain a clear solution. Ethanol was removed at 45-50° C under reduced pressure. 25 ml. of acetone was added and distillation continued to distil ethanol/acetone mixture under reduced pressure. Residue was stirred with 25 ml. acetone at 20-25° C and product filtered under nitrogen atmosphere and washed with 10 ml. acetone. Product was dried 55-60° C under reduced pressure to yield 4.85 g. (89% of theory) Losartan Potassium Form I (DSC).
Example 4
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).
Example 5
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
To a suspension of 5 g. Losartan in 25 ml. n-butanol, 0.75 g. of 86% powdered potassium hydroxide was added and the mixture was stirred at 20-25° C to get a clear solution, n-butanol ethanol was distilled under reduced pressure at temperature below 70° C. 25 ml. acetone was added and distilled under reduced pressure. Finally the contents were stirred in 25 ml. acetone at 20-25° C and filtered to obtain Losartan Potassium Form I. Yield: 4.8 g. (88% of theory).
Example 7
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 polymoφh Form I by addition of ethyl acetate as anti-solvent in place of acetone. Yield: 4.85 g. (89% of theory).
Example 8
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).
Example 9
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).

Claims

We claim:
1. A process to prepare crystalline Form I of Losartan Potassium which comprises
i. Reacting compound of tho formula.
Where "R" represents hydrogen or triphenylmethyl (trityl) protecting group with potassium hydroxide in an alcohol, and
ii. Concentration under reduced pressure to remove alcohol, and
iii. Adding an anti-solvent to isolate Losartan Potassium.
2. A process according to claim 1 wherein exactly one mole equivalent of potassium hydroxide as to the staring compound is used.
3. A process according to claim 1 wherein alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol and mixtures thereof.
4. A process according to claim 1 wherein the anti-solvent is selected from the group consisting of acetone, ethyl acetate, acetonitrile, toluene and mixtures thereof.
5. A process according to claim 1 wherein in situ de-protection is carried out to produce Losartan Potassium.
Dated this 12th day of November, 2001
EP01274254A 2001-05-18 2001-11-20 Process for the crystallization of losartan potassium Withdrawn EP1294712A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN403CH2001 2001-05-18
INMA00001403 2001-05-18
PCT/IN2001/000205 WO2002094816A1 (en) 2001-05-18 2001-11-20 Process for the crystallization of losartan potassium

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EP1294712A1 true EP1294712A1 (en) 2003-03-26

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EP (1) EP1294712A1 (en)
JP (1) JP2004520446A (en)
BG (1) BG107478A (en)
SI (1) SI21236A (en)
SK (1) SK722003A3 (en)
WO (1) WO2002094816A1 (en)

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
AU2003278422A1 (en) * 2002-10-31 2004-05-25 Ranbaxy Laboratories Limited Amorphous form of losartan potassium
ITMI20030328A1 (en) * 2003-02-25 2004-08-26 Dinamite Dipharma S P A In Forma A Bbreviata Diph POLYMORPHS OF LOSARTAN POTASSIUM AND PROCEDURE FOR THEIR PREPARATION.
WO2004076442A1 (en) * 2003-02-28 2004-09-10 Ranbaxy Laboratories Limited Polymorphs of losartan
EP1608641A1 (en) * 2003-04-03 2005-12-28 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
ATE482950T1 (en) * 2003-08-27 2010-10-15 Zentiva Ks METHOD FOR REMOVAL OF TRIPHENYLMETHANE PROTECTING GROUP
ITMI20032472A1 (en) * 2003-12-16 2005-06-17 Dinamite Dipharma S P A In Forma A Bbreviata Diph PROCEDURE FOR THE PREPARATION OF LOSARTAN POTASSIUM CRYSTALLINE
WO2005066158A2 (en) * 2004-01-06 2005-07-21 Ipca Laboratories Limited An improved process for the synthesis of losartan potassium
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
EP1729766A1 (en) * 2004-03-01 2006-12-13 LEK Pharmaceuticals D.D. Pharmaceutical formulation
CA2562597A1 (en) * 2004-05-05 2005-11-24 Marina Yu Etinger 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

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US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
DK0643704T3 (en) * 1991-11-18 2004-01-19 Merck & Co Inc Tetrazolylphenylboronic acid intermediates for the synthesis of All receptor antagonists
PT937068E (en) * 1996-10-29 2002-07-31 Merck & Co Inc PROCESS FOR THE CRYSTALLIZATION OF LOSARTAN
HU222773B1 (en) * 2000-04-21 2003-10-28 Richter Gedeon Vegyészeti Gyár Rt. Process for producing a known tetrazole derivative

Non-Patent Citations (1)

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Title
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SK722003A3 (en) 2003-12-02
BG107478A (en) 2004-01-30
WO2002094816A1 (en) 2002-11-28
SI21236A (en) 2003-12-31
JP2004520446A (en) 2004-07-08

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