WO2008018843A1

WO2008018843A1 - Process for producing useful salts form of biphenyl-tetrazole compounds

Info

Publication number: WO2008018843A1
Application number: PCT/TR2006/000036
Authority: WO
Inventors: Tuncer Aslan; Tuba Bicer; Yildiz Gulkok; Selda Turhan; Melek Koroglu; Serdar Soylemez
Original assignee: Ulkar Kimya Sanayi Ve Ticaret As
Priority date: 2006-08-08
Filing date: 2006-08-08
Publication date: 2008-02-14

Abstract

The invention relates to processes for producing pharmaceutically useful salt form of biphenyl-tetrazole compounds of the following formula by replacement of the acidic tetrazole proton with alkali metal or replacement of the alkali metal of the tetrazole compounds with earth alkali metal and obtaining thereof novel polymorphic forms of sartan salts

Description

DESCRIPTION

PROCESS FOR PRODUCING USEFUL SALTS FORM OF BIPHENYL-

TETRAZOLE COMPOUNDS

This invention relates to a method for producing useful salt forms of biphenyl- tetrazole compounds of the general formula

Wherein

M is a monovalent or divalent cation selected from group consisting OfNa⁺, K⁺, Ca⁺⁺ or Mg⁺* and n is an integer having the value of 1 or 2

R is

R,

-R₁-N

with

R₁ being a straight chain or branched Q-Cβ-alkyl group; and R₂ and R₃ being the same or different and being selected from

-straight-chain or branched, saturated or unsaturated Ci-C₂₀-alkyl groups, which can - optionally be substituted with halogen atoms;

-straight-chain or branched, saturated or unsaturated C₁-C₂o-heteroalkyl groups, which can optionally be substituted with halogen atoms; -aromatic or aliphatic C₃-C₁₈-hydrocarbon rings, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; -aromatic or aliphatic C₃-C₁₈-heterocycles, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; whereby R₂ and R₃ together can form an aromatic or aliphatic C₃-C₁₈-heterocycle, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; reacting a compound of the following formula

)

Wherein R is the same as in Formula (I) and R₄ is a hydrogen or a monovalent cation like sodium or potasium with an alkali or earth alkali metal hydroxide or halogenide selected from the group consisting of NaOH, KOH, Mg(OH)₂, Ca(OH)₂, MgCl₂ or CaCl₂ or their hydrates or alkoxides without use of additional water.

In an embodiment of the invention, the reaction is carried out in an organic solvent or their mixtures. The organic solvents are; Q-Cβ-alcohol, C₃-C₆- ketone, C₃-C₆.ester, C₃-C₇eter or C₅-C₈-hydrocarbon.

Preferably protic solvents, more preferably a C₁-C₆ alcohols and especially an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol and a mixture of C₁-C₆ alcohols with an aprotic solvent selected from the group of ethyl acetate, diethyl ether, tert-butyl methyl ether, pentane hexans or heptane.

It has been shown that for the salt formation reaction protic solvents, particularly alcohols are suitable solvents.

The biphenyl-tetrazole compounds of Formula (I) form among others the backbone of a number of known antihypertensive agents, in which R is for example

Antihypertensive agents comprising such a biphenyl-tetrazole backbone belong to a group of angiotensin II-receptor antagonists which are generally referred to as "sartans". Sartans which show such a biphenyl-tetrazole backbone include Candesartan (R is III), Irbesartan (R is IV), Tasosartan (R is V), Losartan (R is VI), Olmesartan (R is VII) and Valsartan (R is VIII).

These agents work by blocking the action of angiotensin II on its receptor. Angiotensin II mediates among others smooth muscle contraction especially in blood vessels. Angiotensin II receptor antagonists therefore act as powerful vasodilators. The new salt forms of the active pharmaceuticals provide possibilities for the formulation studies and can increase the stability and solubility of the active ingredients in vivo.

Another object of the present invention is to provide alkali metal and earth alkali metal salts of Irbesartan and also a process for producing thereof.

Another object of the present invention is to provide new polymorphic forms of different salts of saltans

BRIEF DESCRIPTION OF THE FIGURES

Fig 1 shows a representative X-ray diffraction pattern of Irbesartan Sodium in amorphous form

Fig 2 shows a representative X-ray diffraction pattern of Irbesartan Potassium in amorphous form

Fig 3 shows a representative X-ray diffraction pattern of Irbesartan Potassium in crystalline form Fig 4 shows a representative X-ray diffraction pattern of Irbesartan Magnesium in amorphous form

Fig 5 shows a representative X-ray diffraction pattern of Irbesartan Calcium in amorphous form

Fig 6 shows a representative X-ray diffraction pattern of Losartan Magnesium in crystalline form

Fig 7 shows a representative X-ray diffraction pattern of Losartan Calcium in crystalline form

Fig 8 shows a representative X-ray diffraction pattern of Valsartan Calcium in crystalline form

The compounds of Formula (II) include precursors to the above sartans that are generally protected by a triphenylmethyl-protecting group and can be obtained deprotection of the protecting group on the tetrazole ring by using an acidic agent. Irbesartan, its salts with acid or bases, methods of making and using them, is first described in EP0454511B1. EP0708103B1 discloses form A and form B of Irbesartan and a process for the preparation thereof. In this publication, the product obtained according to EP0454511 is referred as form A. WO9967236 discloses a new crystalline habit of form A of Irbesartan and a process for the preparation thereof. WO04089938 discloses form C Irbesartan and a process for the preparation thereof. WO03050110 discloses the amorph form of Irbesartan. None of these publications claims the polymorphic forms of different salts of Irbesartan. WO06046043A1 discloses a process for the preparation of Irbesartan HCl in crystalline hydrated or anhydrous form or in amorphous form. No specific alkali or earth alkali metal salts of Irbesartan were described in the prior art.

Losartan is first described in EP0324377B1 in its no salt form. Lately, a process for the preparation of Losartan potassium with potassium hydroxide was described in EP324377B1. Potassium salt of Losartan is known to be the most convenient salt for the formulation. WO 04066997 A2 comprises the earth alkali metal salts of Losartan. The publication describes preparing suitable salt forms of Losartan by using a metal- alkoxide or hydroxide in isopropanol/water. Generally, the mixture is evaporated under reduced pressure to remove the water. Further n-heptane is used as an aprotic solvent to precipitate the Losartan salt. This procedure is almost the same with the patent EP0324377B1. The main problem with these patents is that the given process is complicated due to pH adjustment and removal of the water, which is a time consuming process. Further during the removing of water, side product can be formed.

Valsartan is first described in EP443983B1. Salts of Valsartan was mentioned in EP443983B1 but special properties of specific salts were not mentioned. US 23207930 describes different Valsartan salts as well as salt mixtures thereof. The process described herein comprises the reaction of Valsartan and the appropriate base such as KOH, Mg(OH)₂ and Ca(OH)₂ in a water containing organic solvent. In some cases water had to be removed by adding a co-solvent like toluene and acetonitrile to precipitate the formed salts, which is a time consuming process. At the end step acetonitrile is used which is not a preferable solvent due to the toxicity reasons. Additionally, some cases longer reaction time is necessary to crystallize the salt product.

Both these methods have the problem that they use complicated reaction conditions and procedures. A general simple method is still needed for the preparation of the sartan salts.

It is therefore an object of this invention to describe a general simple method for producing salt forms of biphenyl-tetrazole compounds of formula (I) from compounds of formula (II).

Another object of this invention is the preparation of Ca and Mg salts of saltans, starting from their potassium and sodium salts. The advantage of this process is the elimination of the use of Ca(OH)₂ and Mg(OH)₂ which shows solubility problems.

In one aspect, the present invention is a process for the preparation of alkali metal salts of Irbesartan by using a process comprising following steps: dissolving Irbesartan in an alcohol; dissolving alkali hydroxide in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 ⁰C for 1-4.5 hours; reducing the volume; and in some cases adding the alcohol to an aprotic solvent or directly precipitating; isolating the formed salt by filtration.

In another aspect, the present invention is a process preparing earth alkali metal salts of Irbesartan from alkali metal salts of Irbesartan by replacement of sodium or potassium with magnesium or calcium using a process comprising the following steps: dissolving Irbesartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl₂ or CaCl₂ or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 ⁰C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and some cases adding the polar solvent into an aprotic solvent or directly precipitating; isolating the formed salt by filtration.

In another aspect, the present invention is a process for the preparation of earth alkali metal salts of Losartan from alkali metal salts of Losartan by replacement of sodium or potassium with magnesium or calcium using a process comprising following steps: dissolving Losartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl₂ or CaCl₂ or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 ⁰C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and directly precipitating; isolating the formed salt by filtration.

In another aspect, the present invention is a process for the preparation of earth alkali metal salts of Valsartan from alkali metal salts of Valsartan by replacement of sodium or potassium with magnesium or calcium using a process comprising following steps: dissolving Valsartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl₂ or CaCl₂ or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 ⁰C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and directly precipitating; isolating the formed salt by filtration.

A Rigaku Miniflex X-ray diffractometer is used for the measurements of X-ray diffractograms. The scanning range was 2-40 degrees two-theta. The samples were grounded before analysis.

The water content of the polymorphs and pseudo-polymorphs is measured by using Karl Fischer instrument following method given in the 1990 US Pharmacopoeia at pages 1619-1621 and in European Pharmacopoeia (1992, part 2, sixteen fascicule at v. 3. 5. 6-1). In one aspect, the present invention is a process for preparing Irbesartan Sodium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 1.

In another aspect, the present invention is a process for preparing Irbesartan potassium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 2.

In one aspect, the present invention relates to Irbesartan Potassium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 5.2, 5.7, 6.6,

10.6, 12.5, 12.9, 13.7, 14.8, 16.2, 16.7, 17.5, 18.7, 19.9, 20.6, 21.1, 21.5, 22.1, 22.6, 23.2, 23.6, 24.2, 24.7, 26.1, 26.8, 27.4, 28.4, 29.2, 29.8, 31.9, 32.8, and 36.9 ± 2 degrees two theta and depicted in Figure 3.

In another aspect, the present invention is a process for preparing Irbesartan

Magnesium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 4.

It is also an aspect, the present invention relates to Irbesartan Magnesium in Figure 4 having the water content between about 0.1 % to 10 %, particularly, between about 3

% to 9 % determined by Karl Fischer analysis.

In another aspect, the present invention is a process for preparing Irbesartan Calcium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 5.

It is also an aspect, the present invention relates to Irbesartan calcium in Figure 5 having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.

In one aspect, the present invention relates to Losartan Magnesium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.8, 7.2, 8.3, 11.2, 12.3, 12.9, 13.3, 14.4,14.9, 15.2, 16.5, 17.6, 18.7, 19.2, 20.0, 20.3, 20.9, 21.7, 22.2, 23.3, 23.9, 24.4, 24.9, 25.3, 25.8, 25.9, 27.0, 27.6, 28.4, 28.9, 29.2, 29.8, 30.8, 31.2, 31.8, 32.5, 33.2, 34.0, 35.0, 35.6, 36.2, and 37.2 + 2 degrees two theta as depicted in Figure 6. It is also an aspect, the present invention relates to Losartan Magnesium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.

In one aspect, the present invention relates to Losartan Calcium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.1, 9.36, 10.0, 11.6, 12.5, 13.9, 14.6, 15.5, 16.2, 16.7, 17.1, 18.9, 19.6, 20.4, 21.8, 22.9, 24.0, 25.8, 26.9, 28.7, 30.9, 31.8, and 36.5 ± 2 degrees two theta as depicted in Figure 7. It is also an aspect, the present invention relates to Losartan Calcium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.

In one aspect, the present invention relates to Valsartan Calcium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.0, 9.4, 10.0, 11.6,

12.0, 13.1, 14.1, 14.515.6, 17.1, 17.5, 18.5, 19.2, 20.0, 21.0, 21.9, 22.7, 23.0, 23.9,

24.6, 24.9, 25.3, 26.6, 27.0, 27.4, 28.3, 29.0, 29.3, 30.2, 30.9, 32.1, 33.3, 33.9, 34.9,

37.0, 38.5, and 38.8 + 2 degrees two thetas depicted in Figure 8. It is also an aspect, the present invention relates to Valsartan Calcium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.

In another aspect, the present invention is a process for preparing earth-alkali metal salts of Irbesartan starting from Irbesartan sodium by using a process comprising following steps: dissolving Irbesartan sodium in an alcohol; dissolving MgCl₂ or

CaCl₂ hydrates (Burada or hydrates mi olacak yoksa dogrudan hidratlan ile yapilani mi anlattik? Experimental partta bunlarm kac hydrate oldugu yazih)in the same alcohol and mixing the solutions together; stirring the mixture at 50-70 ⁰C for 1-4.5 hours; reducing the volume; participitating the product between an organic solvent and water; concentrating organic solvent under reduced pressure; stirring for 1-2 hours and isolating the formed salt via filtration. In yet another aspect, the present invention is a process preparing earth-alkali metal salts of losartan starting from Losartan potassium by using a process comprising following steps: dissolving Losartan potassium in an alcohol; dissolving MgCl₂ or CaCl₂ hydrates in the same alcohol and mixing the solutions together; stirring the mixture at 50-70 ⁰C for 1-4.5 hours; reducing the volume; participitating the product between an organic solvent and water; concentrating organic solvent under reduced pressure; stirring for 1-2 hours and isolating the formed salt via filtration.

In an embodiment of the invention, the compound of Formula (I) is a compound that shows angiotensin II -receptor antagonistic activity. Preferably, it is selected from the group consisting of Candesartan, Irbesartan, Losartan, Olmesartan, Tasosartan and Valsartan, whereby Irbesartan, Losartan and Valsartan are particularly preferred.

Such compounds are powerful vasodilators and antihypertensive agents and therefore are of high commercial interest.

In an embodiment of the invention, the reaction is carried in an alcohol, more preferably a C₁-C₆ alcohol especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol by using 0.5 to 1 equivalent of the metal hydroxide or chloride.

It has been shown that for this kind of reaction, particularly alcohols, especially mixture of C₁-C₆ alcohol give the best results with regard to yield as well as solubility of starting materials and metal hydroxide, chlorides and their hydrates.

In a further embodiment of the invention, the method further comprises isolating formed salt of biphenyl tetrazole compounds from the solvent preferably by precipitation. In some cases, it is necessary to use an aprotic solvent like hexane, heptane, ether or ethyl acetate to precipitate the salts. In the case of alkali metal, earth alkali metal replacement reaction an aqueous extraction is necessary to remove formed sodium or potassium chloride then following concentration of organic phase result in precipitation of the desired salts. Precipitation is a particularly preferred method for isolating the formed salts since it can be affected by simply stirring the mixture at room temperature without the need for more complex purification technique such as column chromatography.

In an embodiment of the invention, the solvent is a protic solvent, preferably an alcohol, more preferably a C₁-C₆ alcohol and especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol.

It has been shown that for this kind of reaction, protic solvents, particularly alcohols, especially C₁-C₆ alcohols, give the best results with regard to yield as well as solubility of all agents involved. Methanol, ethanol, and isopropanol have thereby been shown to be the most suitable solvents.

In a further embodiment of the invention, the compound of formula (II) is reacted with the any metal hydroxide or earth alkali hydroxide or chloride, such as of NaOH,

KOH, Mg(OH)₂, Ca(OH)₂, MgCl₂ or CaCl₂ at a temperature from 20 to 80 ⁰C, preferably from 20 to 30 ⁰C.

It has been found that in the above-named temperature ranges, the reactions can be performed in 1.5 to 4.5 hours while obtaining a good yield.

In a further embodiment of the invention, the compound of formula (II) is reacted with the metal hydroxide or earth alkali hydroxides for 1.0 to 4.5 hours, preferably for 1.0 to 3.5 hours.

It has been found that in the above-named time ranges a virtually complete salt formation reaction can be achieved leading to moderate to high yields.

It is understood that the above features and the features described below can be used not only in their described combination but also in other combinations or in isolation without departing from the scope of the invention. The invention is now further illustrated by means of examples. These examples are not intended to limit the scope of the invention any way.

EXAMPLE 1

General Procedure for the Salt Formation Reaction of BiphenvI-Tetrazole

Compounds

(I)

A biphenyl-tetrazole compound of the formula (II) is dissolved in an alcohol. In another flask 0.5 to 1 equivalents of metal hydroxides or chlorides or their hydrates is dissolved in the same alcohol and both solutions are mixed together at 20-80⁰C. After the starting compound with formula (II) is consumed, usually after 1.5 to 4.5 hours, the stirring is stopped. The mixture is concentrated to precipitate the formed salt or evaporated to dryness under reduced pressure or participated between aqueous and organic phases and then precipitated by reducing volume of the organic phase. For further purification, the salt is dissolved in a polar solvent and added drop wise into an apolar solvent and isolated by filtration. EXAMPLE 2

Preparation of Amorphous Irbesartan Na from Irbesartan by using Sodium

Hydroxide

A 100 mL flask was charged with 5.0 g Irbesartan and 20 niL IPA. In another flask 0.47g (leq) NaOH was dissolved in 30 mL IPA at 60 ⁰C. This solution was added to the Irbesartan solution dropwise. The reaction mixture was refluxed for 1.5 h. The mixture was concentrated to 30 mL under reduced pressure. The reaction mixture was refluxed again for 1 h and let to cool to room temperature. 100 mL of tert- butylmethyleter was added to the mixture and it was concentrated to 20 mL. 100 mL of heptane was added and the reaction mixture was heated to 55-60 ⁰C. To precipitate Irbesartan Na the mixture was concentrated under reduced pressure. The mixture was stirred for 1 hour, filtered and washed with heptane. After drying amorphous Irbesartan Na (3.5g) was obtained as a white solid (66 % yield).

EXAMPLE 3

Preparation of Amorphous Irbesartan K from Irbesartan by using Potassium

Hydroxide

A 100 mL flask was charged with 5.0 g Irbesartan and 30 mL IPA. In another flask

0.65 g (leq) KOH was dissolved in 20 mL IPA at 50 ⁰C. This solution was added to the Irbesartan solution dropwise in 5 min. The mixture was refluxed for 1.5 h. The mixture was concentrated under reduced pressure. 100 mL of tert-butylmethyleter was added and the solution was again concentrated under reduced pressure. 100 mL of n-heptane was then added to the solution. To precipitate Irbesartan K the mixture was concentrated under reduced pressure. The mixture was stirred for 1 hour, filtered and washed with heptane. After drying amorphous Irbesartan K was obtained (4.7g) as a white solid (86 % yield).

EXAMPLE 4 Preparation of Crystalline Irbesartan K from Irbesartan by using Potassium

Hydroxide A 100 mL flask was charged with 30.0 g Irbesartan and 100 mL IPA. In another flask 3.92 g (leq) KOH was dissolved in 200 mL IPA at 50 ⁰C. This solution was added slowly to the Irbesartan solution. The mixture was refluxed for 1.5 h. The mixture was concentrated under reduced pressure. 200 mL of tert-butyl methyl ether was added and the solution was concentrated under reduced pressure. The mixture was stirred for 4 hours and then filtered. After drying crystalline Irbesartan K (Form Ul) was obtained (16.4 g) as a white solid (51.4 % yield).

EXAMPLE 5

Preparation of Amorphous Irbesartan Mg starting from Irbesartan Na by using Magnesium Chloride

A 100 niL flask was charged with 2.0 g Irbesartan Na and 10 niL IPA. In another flask 0.45g (0.5 eq) MgCl₂.6H₂O was dissolved in 6 mL IPA and added to the

Irbesartan solution. The mixture was stirred for 1 hour. Water (10 mL) and 100 mL of ethyl acetate was added to the reaction mixture and it is stirred for 30 minutes.

The aqueous phase was washed with another 50 mL ethyl acetate. The ethyl acetate phase was filtered over celite and concentrated under reduced pressure and added to 100 mL of heptane dropwise while stirring. The solid was isolated by filtration and after drying Irbesartan Mg was obtained (1.5g) as a white solid (77 % yield).

EXAMPLE 6 Preparation of Amorphous Irbesartan Ca starting from Irbesartan Na by using

Calcium chloride

A 100 mL flask was charged with 2.0 g Irbesartan Na and 10 mL IPA. In another flask 0.33g (0.5 eq) CaCl₂.2H₂O was dissolved in 2 mL IPA and added to the Irbesartan solution. The mixture was stirred for 1 hour. Water (10 mL) and 100 mL of ethyl acetate was added to the reaction mixture and it was stirred for 30 minutes.

The aqueous phase was washed with another 50 mL ethyl acetate. The ethyl acetate phase was filtered over celite and concentrated under reduced pressure and added to 100 mL of heptane dropwise while stirring. The solid was isolated by filtration and after drying Irbesartan Ca was obtained (1.3g) as a white solid (66 % yield). EXAMPLE 7

Preparation of Crystalline Losartan Mg starting from Losartan Potassium by using Magnesium Chloride

A 100 niL flask was charged with 5.0 g Losartan potassium and 75 mL IPA and the solution was heated to reflux temperature. In another flask 1.1 g (0.5 eq)

CaCl₂.6H₂O was dissolved in 10 mL IPA at room temperature. This solution was added to the Losartan solution. The reaction mixture was stirred for 2 hours at 70-75 ⁰C. The mixture was then concentrated to 10 mL under reduced pressure. 15 mL water and 100 mL of ethyl acetate were added and phases were separated. Organic phase was filtered over celite and to precipitate Losartan Mg, it is concentrated to a volume of 10 mL under reduced pressure. The mixture was stirred for 1 hour, filtered and washed with ethyl acetate. After drying, Losartan Mg (Form Ul) (3.13 g) was obtained as a white solid (65 % yield).

EXAMPLE 8

Preparation of Crystalline Losartan Ca starting from Losartan Potassium by using Calcium Chloride

A 100 mL flask was charged with 5.0 g Losartan potassium and 75 mL IPA and heated to reflux temperature. In another flask 0.89 g (0.5 eq) CaCl₂.2H₂O was dissolved in 10 mL IPA at room temperature. This solution was added to the

Losartan solution. The reaction mixture was stirred for 2 hours at 70-75 C . The mixture was concentrated to a volume of 10 mL under reduced pressure. 5 mL water and 500 mL ethyl acetate were added to the solution to precipitate Losartan Ca. The mixture was then stirred for 1 hour, filtered and washed with mixture of ethyl acetate and water. After drying, Losartan Ca (Form Ul) (3.82 g) was obtained as a white solid ( 78 % yield). EXAMPLE 9

Preparation of Crystalline Valsartan Ca from Valsartan Na by using Calcium

Chloride

In a 100 niL flask 6.Og Valsartan Na was dissolved in 30 niL IPA at room temperature. In another flask 1.83 g (1 eq) CaCl2.2H₂O was dissolved in 1 ImL IPA. This solution was added to the Valsartan Na solution. The mixture was stirred for 30 min. 6 rnL water and 250 mL ethyl acetate was added to the mixture. The aqueous phase was washed two times with ethyl acetate. Valsartan Ca precipitated in ethyl acetate phase, filtered and after drying, Valsartan Ca (Form Ul) (4.0) was obtained as a white solid ( 68 % yield).

Claims

1. Method for producing useful salt forms of biphenyl-tetrazole compounds of the general formula

Wherein

M is a monovalent or divalent cation selected from group consisting of Na⁺, K⁺, Ca⁺⁺ or Mg^+"1" and n is an integer having the value of 1 or 2

R is

-R₁-N

with R₁ being a straight chain or branched Ci-Cβ-alkyl group; and R₂ and R₃ being the same or different and being selected from

-straight-chain or branched, saturated or unsaturated C₁-C₂₀-alkyl groups, which can - optionally be substituted with halogen atoms;

-straight-chain or branched, saturated or unsaturated C₁-C₂₀-heteroalkyl groups, which can optionally be substituted with halogen atoms;

-aromatic or aliphatic C₃-C₁₈-hydrocarbon rings, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; -aromatic or aliphatic C₃-C₁₈-heterocycles, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; whereby R₂ and R₃ together can form an aromatic or aliphatic C₃-C₁₈-heterocycle, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; reacting a compound of the following formula

Wherein R is the same as in Formula (I) and R₄ is a hydrogen or a monovalent cation like sodium or potasium with an alkali or earth alkali metal hydaroxide or halogenide selected from the group consisting of NaOH, KOH, Mg(OH)₂, Ca(OH)₂, MgCl₂ or CaCl₂ or their hydrates or alkoxides without use of additional water.

2. Method according to claiml, characterized in that R₂ and R₃ together form an imidazole ring, which can be substituted or unsubstituted, part of a fused ring system and partially or fully hydrogenated.

3. Method according to claiml, characterized in that R₂ and R₃ are alkyl groups comprising at least one carboxy or alkoxy group.

4. Method according to any one of the claims 1 to 3, characterized in that R₁ is -CH₂-.

5. Method according to any one of the claims 1 to 4, characterized in that the compound of formula (I) is a compound that shows angiotensin II-receptor antagonistic activity.

6. Method according to any one of the claims 1 to 5, characterized in that the compound of formula (I) is selected from the group consisting of Candesartan, Irbesartan, Losartan, Olmesartan, Tasosartan and Valsartan; preferably Irbesartan, Losartan and Valsartan.

7. Method according to any one of the claims 1 to 6, characterized in that alkali or earth alkali metal hydroxide or halogenide are NaOH, KOH, MgCl₂ or CaCl₂ or their hydrates or alkoxides.

8. Method according to any one of the claims 1 to 7 characterized in that the compound of formula II is reacted with the alkali metal hydroxide or earth alkali metal hydroxide or chloride at a temperature from 20 to 85 ⁰C, preferably from 20 to 30 ⁰C.

9. Method according to any one of the claim 1 to 8, characterized in that the compound of formula II is reacted with the alkali metal hydroxide or earth alkali metal hydroxide or chloride for 1.0 to 4.5 hours, preferably 1.5 to 3.5 hours.

10. Method according to any one of the claims 1 to 9 , characterized in that salt forms of biphenyl-tetrazole compounds of the general formula I is prepared by using a process comprising following steps: a) dissolving biphenyl-tetrazole compound of formula II in an alcohol; b) dissolving metal hydroxides or chlorides or their hydrates in the same alcohol and mixing the solutions together; c) stirring the mixture at 20-80 ⁰C for 1.5-4.5 hours; d) concentrating the mixture to precipitate the formed salt or evaporating the mixture to dryness under reduced pressure or participating the mixture between an aqueous and an organic solvent and then precipitating the salt by reducing volume of the organic phase or by adding organic phase containing the product drop wise into an apolar organic solvent and isolating the product by filtration.

11. Method according to claim 10, characterized in that the solvent is an organic solvent or their mixtures.

12. Method according to claim 11, characterized in that the organic solvent is C_t-C_ό-alcohol, C₃-C₆-ketone, C₃-C₆.ester, C₃-C₇eter or C₅-C₈-hydrocarbon.

13. Method according to claim 12 characterized in that the organic solvent is selected from the group of isopropanol, methanol, ethanol, acetone, methylisobutylketone tert- butylmethylketone, ethyl acetate, diethyl eter, diisopropyl eter, tertiarybutylmethyl eter, heptane, hexanes and heptane.

14. Earth alkali and Alkali metal salts of Irbesartan.

15. Earth alkali metal salts of claim 14 are calcium and magnesium.

16. Alkali metal salts of claim 14 are sodium and potassium.

17. A process for preparing alkali metal salts of Irbesartan comprising the steps of: a) dissolving Irbesartan in an alcohol; b) dissolving alkali hydroxide in the same alcohol and mixing the solutions together; c) stirring the mixture at 20-85 ⁰C for 1-4.5 hours; d) reducing the volume, and some cases adding the alcohol to an aprotic solvent or directly precipitating; isolating the formed salt by filtration.

18. The process of claim 17 wherein alkali metal salts of Irbesartan are sodium and potassium.

19. Sodium salt of Irbesartan in amorphous form characterized by having a powder X-ray diffraction pattern substantially as depicted in Figure 1 where water content is between about 0.1% to 10%.

20. Potassium salt of Irbesartan in amorphous form characterized by a having a powder X-ray diffraction pattern substantially as depicted in Figure 2 where water content is between about 0.1 % to 10% .

21. Potassium salt of Irbesartan in crystalline form Ul characterized by having X-ray diffraction peaks (reflections) at about 5.2, 5.7, 6.6, 1 0.6, 12.5, 12.9, 13.7, 14.8, 16.2, 16.7, 17.5, 18.7, 19.9, 20.6, 21.1, 21.5, 22.1, 22.6, 23.2, 23.6, 24.2, 24.7, 26.1, 26.8, 27.4, 28.4, 29.2, 29.8, 31.9, 32.8, and 36.9 ± 2 degrees two theta.

22. Potassium salt of Irbesartan in crystalline form Ul according to claim 23 characterized by having a powder X-ray diffraction pattern substantially as depicted in Figure 3 and having a water content between about 0.1% to 10% by weight.

23. A process for preparing earth alkali metal salts of saltans from alkali metal salts of saltans by replacement of sodium or potassium with magnesium or calcium comprising the steps of: a) dissolving alkali metal salts of sartans in an alcohol; b) dissolving earth alkali metal chloride such as MgCl₂ or CaCl₂ or their hydrates in the same alcohol and mixing the solutions together; c) stirring the mixture at 20-85 ⁰C for 1-4.5 hours; d) participitating the product between an organic solvent and aqueous solvent, reducing volume of organic solvent containing desired product and precipitating; isolating the formed earth alkali salt of the product by filtration.

24. The process according to claim 23, characterized in that sartans are Irbesartan, Losartan and Valsartan.

25. The process according to any one of claims 23 to 24, characterized in that alcohol is Ci-Cβ-alcohol.

26. The process of claim 25 wherein said C₁-C₆ alcohol is methanol, ethanol, propanol, isopropanol.

27. The process according to any one of claims 23 to 26, characterized in that solvent is an organic solvent or their mixtures.

28. The process of claim 27 wherein said organic solvent is Q-Ce-alcohol, C₃- C₆-ketone, C₃-C₆.ester, C₃-C₇ether or Cs-Cs-hydrocarbon.

29. The process of claim 28 wherein said C;ι-C₆-alcohol, C₃-C₆-ketone, C₃-C₆. ester, C₃-C₇-ether or C₅-C₈-hydrocarbon is selected from the group consistingof isopropanol, methanol, ethanol, acetone, methylisobutylketone tertiary- butylmethylketone, ethyl acetate, diethyl ether, diisopropyl ether, førriαrμbutylmethyl ether, pentane, hexanes and heptane.

30. Magnesium salt of Irbesartan in amorphous form characterized by a powder

X-ray diffraction pattern substantially as depicted in Figure 4 and having water content between about 0.1% to 10%, especially between 4% and 8% by weight.

31. Calcium salt of Irbesartan in amorphous form characterized by a powder X- ray diffraction pattern substantially as depicted in Figure 5 and having water content between about 0.1% to 10%, especially between 4% and 8% by weight.

32. Losartan Magnesium in crystalline form Ul characterized by having X-ray diffraction peaks (reflections) at about 6.8, 7.2, 8.3, 11.2, 12.3, 12.9, 13.3, 14.4,14.9, 15.2, 16.5, 17.6, 18.7, 19.2, 20.0, 20.3, 20.9, 21.7, 22.2, 23.3, 23.9, 24.4, 24.9, 25.3,

25.8, 25.9, 27.0, 27.6, 28.4, 28.9, 29.2, 29.8, 30.8, 31.2, 31.8, 32.5, 33.2, 34.0, 35.0, 35.6, 36.2, and 37.2 ± 2 degrees two theta.

33. Losartan Magnesium in crystalline form Ul according to claim 32 characterized by having a powder X-ray diffraction pattern substantially as depicted in Figure 6 and having a water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 %.

34. Losartan Calcium in crystalline form Ul characterized by having X-ray diffraction peaks (reflections) at about 6.1, 9.36, 10.0, 11.6, 12.5, 13.9, 14.6, 15.5, 16.2, 16.7, 17.1, 18.9, 19.6, 20.4, 21.8, 22.9, 24.0, 25.8, 26.9, 28.7, 30.9, 31.8, and 36.5 ± 2 degrees two theta.

35. Losartan Calcium in crystalline form Ul according to claim 34 characterized by having a powder X-ray diffraction pattern substantially as depicted in Figure 7 and having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 %.

36. Valsartan Calcium in crystalline form Ul characterized by having X-ray diffraction peaks (reflections) at about 6.0, 9.4, 10.0, 11.6, 12.0, 13.1, 14.1, 14.515.6, 17.1, 17.5, 18.5, 19.2, 20.0, 21.0, 21.9, 22.7, 23.0, 23.9, 24.6, 24.9, 25.3, 26.6, 27.0, 27.4, 28.3, 29.0, 29.3, 30.2, 30.9, 32.1, 33.3, 33.9, 34.9, 37.0, 38.5, and 38.8 + 2 degrees two thetas.

37. Valsartan Calcium in crystalline form Ul according to claim 36 characterized by having a powder X-ray diffraction pattern substantially as depicted in Figure 8 and having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 %.