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

Definitions

• This invention relates to improvement in process for preparation of Losartan Potassium as claimed in our main application. More specifically this invention relates to a commercial process for preparation of the polymorphic Form I of Losartan potassium and an improvement in use of reagent in the reaction and conditions thereof for the preparation of the said Losartan Potassium as claimed in our main application as above.
• Losartan potassium plays an effective role in patients having difficulty in tolerating ACE inhibitors.
• the chemical name of Losartan potassium is 2-n-Butyl-4- Chloro- 1 - [((2 ' -tetrazol-5 -yl)-l , 1 ' -bisphenyl-4-y l)methyl] -imidazole-5 -methanol potassium.
• Losartan potassium (shown as the compound of Formula (I) below) is known in the art is synthesized by reacting its acid (shown as the compound of formula (II) below) with KOH.
• the intermediate acid Formula (II) in turn is synthesized by detritylation of 2- n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyltetrazole-5-yl) biphenyl-4-yl) methyl] imidazole (shown as the compound of Formula (III) below)
• Trityl Losartan (the reactant of Formula (III) below) is known in the art. See 34 J. MED. CHEM. 2525-27 (1991); 59 J. ORG. CHEM. 6391-94 (1994); US 5,138,069. Trityl Losartan (and the Losartan acid/free Losartan) and may alternatively be prepared using the reactions and techniques described in US Patent 5,138,069 and patent application number W093/10106.
• Trityl Losartan the reactant of Formula (III) of Losartan acid (II) by acid-catalyzed cleavage of trityl group from Trityl Losartan (III) is disclosed in US 5,281,603.
• Another method disclosed to prepare Losartan acid from trityl Losartan is disclosed in US 5,281,604.
• Trityl Losartan (III) is refluxed in a mixture of methanol and tetrahydrofuran in presence of catalytic acid like hydrochloric acid for 18 hours to get Losartan acid (II).
• Patent application number WO98/18787 describes a method, which also starts with a solution of Losartan Potassium (I) in aqueous isopropyl alcohol and is heated to distill out water-isopropyl alcohol mixture to lower the water content to 2.6%. Further excessive seeding is carried out with slurry of Losartan Potassium (I) in cyclohexane until the seed remains undissolved. The Precipitation of the product is then achieved by continuous distillation of ternary azeotrope with simultaneous addition of cyclohexane to the reaction mass. This azeotrope distillation is carried out until moisture level decreases to about 0.2 to 0.11%. The crystallized product thus obtained is filtered.
• the present invention avoids the use of stringent azeotropic distillation of water from the reaction mass to precipitate Losartan potassium. Also it avoids the use of antisolvents for the removal of water or for the precipitation of Losartan teachingassium as taught by the prior art.
• the Richter Gedeon approach was found to be easy and superior to the existing methods, however was found to suffer from various drawbacks as summarized below: a) The product obtained does not pass desired solubility in various solvents. To make the product improve in quality, it needs an extra purification as per the Richter Gedeon application. b) Purification step in the process, the resultant purity and the yields thereof, depends on very precise ratios of solvent mixture (e.g. methanol, cyclohexane or acetonitrile). c) High volume of solvents and that too in very precise combination in purification which leads to capacity reduction of plant production/facilities.
• solvent mixture e.g. methanol, cyclohexane or acetonitrile
• Patent application number WO 02/094816 discloses use of acetone, ethyl acetate, acetonitrile and toluene as anti-solvents and has similar problems of recovery and reuse of solvents and high cost of production. Since isolation of the product is simply by precipitation using anti solvents, the product needs further purification to pass the required tests, in this case also.
• polymorphic Form I is the addition of aqueous solution of (I) to a refluxing mixture of cyclohexane and isopropyl alcohol followed by azeotropically distilling out cyclohexane /isopropyl alcohol/water ternary azeotrope at 64°C while the Form I crystallizes out at 69°C.
• FIG. 1 Powder X-Ray Diffraction (PXRD) pattern of Losartan potassium Form I produced from Tetra ydrofuran as solvent.
• Figure 2. Powder X-Ray Diffraction (PXRD) pattern of Losartan potassium Form I produced from Isopropyl alcohol as solvent.
• Figure 3. Differential Scanning Calorimeter (DSC) thermogram of Losartan potassium Form I produced from Tetrahydrofuran as solvent.
• Figure5. FTIR spectrum of Losartan potassium Form I produced from Tetrahydrofuran as solvent from 1150 cm “1 to 600 cm “1 .
• Figure 6. FTIR spectrum of Losartan potassium Form I produced from Tetrahydrofuran as solvent from 1800 cm “1 to 1150 cm “1 .
• the present invention relates to an improvement in the user friendly use of the reagent in reaction and the reaction conditions for the preparation of Losartan Potassium as claimed in our main application as mentioned above. Additionally it provides process for preparation of polymorphic Form I of Losartan potassium.
• the primary reagent in this invention is potassium tertiary butoxide, which is hygroscopic, air sensitive and a fluffy powder. To avoid contact with moisture, the operation using pure dry potassium tertiary butoxide needs to be carried out under nitrogen atmosphere. Handling of potassium tertiary butoxide on large scale in powder form may lead to flying of the reagent and is dangerous to the operating personnel. These problems of handling can be overcome by using Potassium tertiary butoxide in solution form as the reagent.
• the improved process for preparation of Losartan Potassium by reacting, in primary alcohol such as methanol, a solution of Potassium tertiary butoxide in tertiary butanol with equimolar quantities of Trityl Losartan is disclosed.
• a solution of potassium tertiary butoxide in isopropyl alcohol is reacted in methanol with Trityl Losartan.
• Potassium tertiary butoxide is used as a solution in secondary or tertiary alcohol.
• a process for the synthesis of Losartan Potassium comprising reacting approximately equimolar quantities of Potassium salts such as potassium tertiary butoxide as a solution in a secondary / tertiary alcohol with Trityl Losartan in methanol; refluxing the reaction mixture to obtain a reaction mass comprising Losartan Potassium; momtoring the completion of reaction using TLC; concentrating the reaction mass to approximately 50 %; cooling the reaction mass to approximately -5° C; distilling out the methanol from the reaction mixture; stripping of methanol from the reaction mixture using solvents like isopropyl alcohol or tetrahydrofuran; maintaining the reaction mass in said solvent for approximately 12 hours at 25 to 30° C; cooling the reaction mixture to 0-5° C; filtering out Losartan potassium; washing with chilled Isopropyl alcohol and drying the Losartan Potassium under vacuum.
• Potassium salts such as potassium tertiary butoxide as a solution in a secondary / tert
• the secondary or tertiary alcohol used for the preparation of potassium tertiary butoxide solution is isopropyl alcohol and tertiary butanol.
• the preferred strength of the potassium tertiary butoxide solution is 15 to 25% (w/v); most preferred strength is 15 to 20% (w/v).
• potassium salts such as anhydrous potassium carbonate in a primary or secondary alcohol
• Trityl Losartan is reacted with Trityl Losartan to yield Losartan Potassium in high yields.
• a process for manufacture of Losartan potassium comprising reacting equimolar quantities of anhydrous alkali metal salt in methanol with approximately 1 mole Trityl Losartan; refluxing the reaction mixture for 10 to 15 hours; monitoring the completion of reaction using TLC; concentrating the reaction mass to approximately 50 %; cooling the reaction mass to approximately -5° C; distilling out the methanol from the reaction mixture; stripping of methanol from the reaction mixture using solvents like isopropyl alcohol or tetrahydrofuran; maintaining the reaction mass in said solvent for approximately 12 hours at 25 to 30° C; cooling the reaction mixture to 0-5° C; filtering out Losartan potassium; washing with chilled Isopropyl alcohol and drying the Losartan Potassium under vacuum.
• potassium salts used are selected from anhydrous potassium carbonate and potassium bicarbonate.
• the primary or secondary alcohols u ⁇ ed in the invention as the reaction media includes methanol, ethanol and isopropyl alcohol. This process of replacing potassium tertiary butoxide with these potassium salts has substantial advantages in terms of cost on a manufacturing scale.
• the Losartan potassium obtained after removal of triphenyl methyl ether was concentrated and the solvent is chased using solvent such as tetrahydrofuran (THF) or a mixture thereof with IPA.
• THF tetrahydrofuran
• the THF layer was refluxed for a period of 0.5 - 3 hours followed by cooling of the solution to a temperature of 25 - 30°C and kept at this condition for a period of 10 - 15 hours.
• the reaction mass was then chilled to a temperature of 0-5°C. There after the precipitated crystals filtered and dried, the crystals are identical with the polymo ⁇ hic Form I of Losartan potassium.
• the crystal form was identified by differential scanning calorimetry and X -Ray powder diffraction patterns.
• the polymo ⁇ h Form I was prepared by the following steps comprising reacting Trityl Losartan with equimolar quantity of anhydrous potassium carbonate in methanol; refluxing the resultant mixture for a period of 7 - 12 hours; concentrating methanol to half volume; filtering triphenyl methyl methyl ether; concentrating the methanol mixture to 50% volume; removing residual solvent using solvents like isopropyl alcohol, tetrahydrofuran (THF) or its mixture thereof and keeping the mass at 25-30°C for aging the crystal growth for a period of 10 - 15 hours; chilling the said solvent layer to a temperature of 0-5°C to precipitate the crystals of polymo ⁇ h I and filtering the said precipitated crystals of polymo ⁇ h Form I.
• THF tetrahydrofuran
• the process for manufacture of polymo ⁇ h Form I of Losartan potassium comprising dissolving Losartan potassium obtained after detritylation, in solvent tetrahydrofuran or its mixture thereof with solvents such as isopropyl alcohol at reflux; cooling to a temperature of 25-30°C; aging the crystal at this temperature for a period of 7-13 hours and cooling the mass to a temperature of 0-5°C.
• solvents such as isopropyl alcohol at reflux
• tetrahydrofuran is used to dissolve Losartan potassium obtained after detritylation in the said manufacturing process of Polymo ⁇ h Form I of Losartan potassium.
• Losartan potassium polymo ⁇ h Form I was obtained by changing the base to potassium tertiary butoxide in place of potassium carbonate.
• the reaction mass is then cooled to 0 - 5°C and filtered.
• the resulting product, Losartan Potassium is then washed with chilled isopropyl alcohol (45 ml.).
• the final product is dried at 35-50°C under vacuum for 6 hours to remove residual isopropyl alcohol.
• the percentage yield of Losartan Potassium/orm / is 81%.
• Isopropyl alcohol (225 ml) is charged, refluxed for 1 hour, cooled and kept for 12 hours at 25-30°C. The reaction mass is then cooled to 0 - 5°C and filtered. The resulting product, Losartan Potassium is then washed with chilled isopropyl alcohol (45 ml). The final product is dried at 35-50°C under vacuum for 6 hours to remove residual isopropyl alcohol. The percentage yield of Losartan Potassium form /is 82%.
• the reaction mass is then chilled to 0 - 5°C and filtered.
• the resulting product, Losartan Potassium is then washed with chilled tetrahydrofuran(45 ml).
• the final product is dried at 35-50°C under vacuum for 6 hours to remove residual tetrahydrofuran.
• the percentage yield of Losartan Potassium or / is 90 %.

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• Chemical & Material Sciences (AREA)
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• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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