SI21236A - Process for the crystallization of losartan potassium - Google Patents

Abstract

There is disclosed a process to prepare crystalline form (I) of Losartan Potassium which comprises: i) reacting of losartan acid or a compound of trityl losartan of formula (II), where "R" represents hydrogen or triphenylmethyl (trityl) protecting group with potassium hydroxide in an alcohol selected from a group which comprises methanol, ethanol, propanol, butanol or mixtures thereof, and ii) concentration under reduced pressure to remove alcohol, and iii) adding an anti-solvent selected from a group which comprises acetone, ethyl acetate, toluene or mixtures thereof to isolate Losartan Potassium.

Description

AUROBINDO PHARMA LIMITED

India

LOSARTAN POTASSIUM CRYSTALIZATION PROCEDURE

The invention relates to a crystallization process for the preparation of Losartan Potassium in Form I. Losartan Potassium is also known as n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (2H10 tetrazol-5-yl) biphenyl-4 -yl] methyl] imidazole potassium salt and is used in the treatment of high blood pressure.

Losartan is known to inhibit the action of the octapeptide hormone angiotensin II and is therefore useful in relieving angiotensin-triggered hypertension. It was further observed that Losartan, taken together with a diuretic such as furosemide or hydrochlorothiazide, has a potent antihypertensive effect. Administration of Losartan with a non-steroidal anti-inflammatory drug may prevent renal failure.

Losartan is known to be polymorphic (Source: US Patent 5,608,075). Two Losartan Potassium polymorphs, Form I and Form II, have been described in the patent

US 5,608,075 together with methods for their preparation. The labeling of these two polymorphic forms has been described using X-ray diffraction patterns, DSC thermograms, FTIR spectra, Raman spectra and ¹³ C solid state NMR.

Polymorph Form I was prepared in US Patent 5,608,075 by adding an aqueous solution of Losartan Potassium to reflux the isopropanol / cyclohexane mixture and remove water by distilling the ternary azeotrope of cyclohexane / isopropanol / water at 64 ° C. Losartan Form I potassium crystallized at 69 ° C.

WO 98/18787 discloses a process for the preparation of polymorphic Form I whereby the potassium salt solution in aqueous isopropanol solution is heated to reduce the water content to about 2.6% by removing the isopropanol / water mixture. A strong sludge screening with Losartan Potassium in cyclohexane io was carried out until the starting material remained undissolved and then water was removed to 0.02-0.11% by distillation of the ternary azeotrope while cyclohexane was added at the same time. The crystallized material was recovered by filtration.

In both disclosed processes, crystalline Losartan Potassium was produced from a mixture of isopropanol and cyclohexane, and this crystalline material was designated as polymorph Form I. The crystallization process described in WO 98/18787 requires adequate precision to obtain polymorph Form I consistently. , cyclohexane and isopropanol are difficult to separate. The inventors have surprisingly discovered that Losartan Potassium with polymorph Form I can be prepared in one pot by reacting triphenylmethyl protected Losartan with potassium hydroxide in methanol / acetone without isolating free Losartan acid, and does not require screening.

According to the invention, a process for crystallizing Losartan Potassium of the formula is provided

which comprises

i) reacting Losartanic acid or the compound Trityl Losartan of formula II,

wherein 'R' represents hydrogen or triphenylmethyl (trityl) protecting group with 20 potassium hydroxide in an alcohol selected from the group comprising methanol, ethanol, propanol, butanol and mixtures thereof, and ii) concentrating under reduced pressure to remove alcohol , and iii) adding an anti-solvent selected from the group comprising acetone, ethyl acetate, acetonitrile, toluene and mixtures thereof to isolate Losartan Potassium.

In this process, exactly one mole of potassium 5 hydroxide equivalent is used relative to the starting material.

The invention relates to a process for the manufacture of Losartan Potassium Form I without the use of an isopropanol / cyclohexane solvent mixture. Usually, the free acid of Losartan is immersed in the solvent and potassium hydroxide is added to give 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. Solvents for the preparation of Losartan Potassium include methanol, ethanol, butanol, but salt formation is preferably carried out in methanol. The anti-solvent is selected from conventional solvents such as ethyl acetate, acetonitrile, toluene and acetone, but the most preferred solvent is acetone.

Losartan free acid or triphenylmethyl protected Losartan can be prepared using the reactions and techniques described in US Patent 5,138,069 and WO 93/10106.

Alternatively, n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- [(2-triphenylmethyl) tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole (referred to herein as Trityl Losartan), a key intermediate in the manufacture of Losartan,

refluxed with potassium hydroxide in alcohol, preferably methanol, to remove the protection and form the original Losartan Potassium, which is then isolated to the desired polymorph Form I by distilling methanol and the addition of an anti-solvent such as acetonitrile, toluene, ethyl acetate and after options acetone. The reaction and crystallization can both proceed in the same reaction vessel and no expensive separation techniques are required such as the elimination or isolation of Losartan free acid. Such a process for the production of Losartan Potassium with polymorphic Form I directly from Trityl

Losartan has so far not been described in the literature and therefore represents the subject of the present embodiment. In addition, the described preparation is essentially carried out under water-free conditions, thus avoiding complex azeotropic distillation to remove water. The desired polymorphic form I of Losartan Potassium is obtained directly, that is, without the isolation of Losartan free acid, which allows for higher efficiency and contributes to lower production costs.

Usually, Tritil Losartan is dissolved in 6-8 volume units in methanol and an equimolar amount of potassium hydroxide is added. The resulting mixture was refluxed for several hours until Tritil Losartan disappeared. Tritanol is recovered by filtration and the methanol is distilled off under reduced pressure. Acetone was added to the residue and further methanol residues were removed by further distillation. Losartan Potassium is obtained as free-flowing sludge in acetone, which is filtered and dried. Differential scanning calorimetric analysis and X-ray diffraction pattern confirm that this is a polymorphic modification of I.

The following examples further illustrate the preparation of Losartan Potassium with polymorphic Form I and do not imply any restrictions.

⁵ Example 1

100 g (0.152 mol) of n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- [(2-triphenylmethyl) tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole (Trityl Losartan) was immersed in 650 ml of methanol. 10 g of 85% potassium hydroxide (0.152 mol) were added and the mixture was refluxed under nitrogen for almost 6 hours. The reaction mass of io was cooled to 8-10 ° C and the tritanol by-product was removed by filtration and washed with 50 ml of chilled methanol. The filtrate was treated with 1 g charcoal and filtered through celite. The methanol solution of the session was then concentrated at 45-50 ° C to remove most of the methanol. 200 ml of acetone was added and distillation was continued under reduced pressure to reduce the volume to ca.

120 ml. The white crystalline sludge was cooled to room temperature, filtered and the product was washed with 50 ml of acetone and dried in a vacuum oven to give Losartan Potassium. Yield: 60 g (86.58% of theory). DSC analysis and X-ray diffraction pattern match the report for polymorphic Form I.

Example 2

Suspension of 5 g (11.82 mole) of n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (2Htetrazol-5-yl) biphenyl-4-yl] methyl] imidazole (Losartanic acid ) in 25 ml of methanol, 0.75 g (86%) (11.52 mole) of potassium hydroxide in powder form was added

-7and the mass was stirred at room temperature to give an almost clear solution. This was filtered through celite and the purified solution concentrated to remove most of the methanol at 45-50 ° C under reduced pressure. 25 ml of acetone was added and distillation continued to distill most of the methanol / acetone mixture. The residue was distilled off with 25 ml of acetone, the contents cooled to 20-25 ° C for 10 minutes and the product filtered under nitrogen and washed with 5 ml of acetone. The product was dried at 55-60 ° C under reduced pressure to give 4.88 g (89.5% of theory) of Losartan Potassium Form I (DSC, XRPD).

Example 3

To a suspension of 5 g (11.82 mole) of Losartanic acid in 25 ml of dry ethanol was added 0.75 g (86%) (11.52 mole) of potassium hydroxide in powder form and stirred for 25 minutes. at room temperature to give a clear solution.

The ethanol was removed at 45-50 ° C under reduced pressure, 25 ml of acetone was added and the distillation of the ethanol / acetone mixture under reduced pressure was continued. The residue was mixed with 25 ml of acetone at 20-25 ° C and the product was filtered under a nitrogen atmosphere and washed with 10 ml of acetone. The product was dried at 55-60 ° C under reduced pressure to give 4.85 g (89% of theory) of Losartan Potassium Form I (DSC).

Example 4

Losartan Form I potassium was prepared from Losartan acid and methanol as described in Example 2 and ethyl acetate was used instead of acetone.

Yield: 4.95 g (91% of theory).

Example 5

Losartan Form I potassium was prepared from Losartan acid according to the procedure described in Example 2 and acetonitrile was added as a solvent for isolating the io product. Yield: 4.8 g (88% of theory).

Example 6

To a suspension of 5 g of Losartanic acid in 25 ml of n-butanol, 86% of potassium hydroxide powder was added and the mixture was stirred at 20-25 ° C to give a clear solution. n-Butanol was distilled under reduced pressure at a temperature below 70 ° C. 25 ml of acetone was added and distilled under reduced pressure. Finally, the contents were mixed in 25 ml of acetone at 20-25 ° C and filtered to give Losartan Potassium Form I. Yield: 4.8 g (88% of theory).

Example 7

Losartan Potassium was prepared by reacting Losartanic acid in nbutanol with potassium hydroxide as described in Example 6, and the product was isolated as polymorph Form I by the addition of ethyl acetate as an anti-solvent instead of acetone. Yield: 4.85 g (89% of theory).

Example 8

Losartan Potassium was prepared in n-butanol as described in Example 6, and Form I 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 io form I was obtained by the addition of acetonitrile. Yield: 4.8 g (88% of theory).

Claims (3)

PATENT APPLICATIONS A process for the preparation of crystalline Form I of Losartan Potassium of Formula I comprising Formula I i) responding Losartanic acids or Trityl Losartan compounds of formula II wherein 'R' represents hydrogen or triphenylmethyl (trityl) protecting group with potassium hydroxide in an alcohol selected from the group consisting of methanol, 20 ethanol, propanol, butanol and mixtures thereof, to remove the protection if present; concentrating under reduced pressure to remove alcohol; and Iii) adding an anti-solvent selected from the group consisting of acetone, ethyl acetate, acetonitrile, toluene and mixtures thereof. The process of claim 1, using exactly one mole of potassium hydroxide equivalent 5 as the starting compound. The method of claim 1, wherein the deprotection is for the manufacture of Losartan Potassium.