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

wherein

with

R ₁ being a straight chain or branched C _j :-C ₆ -alkyl group; and

R ₂ and R ₃ being the same or different and being selected from

straight-chain or branched, saturated or unsaturated C ₁ -C ₂₀ -^IkYl groups, which can optionally be substituted with halogen atoms; straight-chain or branched, saturated or unsaturated ^c i- ^C ₂₀ -heteroalkyl groups, which can optionally be substituted with halogen atoms; aromatic or aliphatic C ₃ -C ₁₈ -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 C ₃ -C ₁₈ -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 R ₂ and R ₃ together can form an aromatic or aliphatic C ₃ -C ₁₈ -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; comprising reacting a compound of the following formula

(II)

wherein R is the same as in formula (I), with a deprotecting agent in a solvent.

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 Cande- sartan (R is IV), Irbesartan (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 compounds of formula (II) include precursors to the above sartans which are protected by a triphenylmethyl-protecting group. This group is commonly also referred to as a trityl- protecting group and has the following formula

It is generally represented in the above and below formulas as

Ph ₃ C.

The compounds of formula (II) are formed as intermediates in the synthesis of the corresponding sartans of formula (I). In a further step, they need to be deprotected in order to form the desired active compounds.

EP 0 733 366 Bl describes the removal of the trityl-protecting group by treating the trityl-protected precursor of Losartan with hydrochloric acid (Example 316).

It is further known from WO 03/093262 A2 with respect to Losar- tan that the trityi-protecting group can be removed using an acid in a diluent comprising a liquid ketone.

Both these methods have the problem that they use large amounts of highly corrosive substances which are difficult to handle and can cause severe environmental problems .

The use of strong acids in the deprotection of larger organic compounds further carries the risk of degrading some of the starting and/or target compounds leading to a reduced yield.

It is therefore an object of this invention to describe a new method for producing biphenyl-tetrazole compounds of formula (I) from compounds of formula (II) which can be effected without the use of strong acids as deprotecting agents.

It was now surprisingly found that certain hydroxy1ammonium salts can be successfully used to deprotect the trityl-protect- ed biphenyl-tetrazole compounds of formula (II).

The object is therefore achieved by a method for producing compounds of formula ( I ) wherein the deprotecting agent is a compound of the following formula

wherein R ₄ , R ₅ are the same or different and hydrogen or straight-chain or branched groups and wherein A is an organic or inorganic monovalent anion.

These compounds act as a source of H ⁺ -ions to remove the tri- tyl-protecting group, but do so at a more moderate pH value than the agents used previously. They also form hydroxylammo- nium compounds as by-products which can be easily removed by distillation, they can for example be removed together with the solvent at the end of the reaction.

The reaction of this method therefore proceeds with high yields and results in an easily purified product. The compounds of formula (III) employed are less corrosive and much easier to handle than e.g. strong mineral acids due to their more moderate pH-value .

Preferably, R ₂ and R ₃ either together form an imidazole ring, which can be substituted or unsubstituted, part of a fused ring system and partially or fully hydrogenated, or R ₂ and R ₃ are alkyl residues comprising at least one carboxy group.

R ₁ is preferably -CH ₂ -.

Compounds of such a structure are known to show biological activity and therefore are of interest in the synthesis of active ingredients for various pharmaceuticals .

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, and VaI- sartan, whereby Irbesartan and Losartan are particularly preferred.

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

In a further embodiment of the invention, R ₄ and R ₅ are both hydrogen .

A is preferably a monovalent anion of a mineral acid. More preferably the compound of formula (III) is selected from the group consisting of hydroxylammonium sulfates and hydroxylammo- nium chlorides.

Compounds of formula (III) in which R ₄ and R ₅ are both hydrogen and/or A is a monovalent anion of a mineral acid in general and hydroxylammonium sulfates and hydroxylammonium chlorides in particular have been shown to give good results in the depro- tection of the compounds of formula (II). They are also relatively inexpensive and readily available compounds, making them well suited to a large scale use.

In an embodiment of the invention, the solvent is a protic solvent, preferably an alcohol, more preferably a 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 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 .

The use of alcohols as solvents further has the advantage that trityl-methanol which is formed during the deprotection reaction readily precipitates from such solvents, further facilitating the purification of the desired product.

In a further embodiment of the invention, the method further comprises isolating formed trityl-methanol from the solvent, preferably by precipitation.

The trityl-protecting group is removed from the biphenyl- tetrazole compounds of formula (II) in form of trityl-methanol. The trityl-methanol is formed by the reaction of the trityl- cation formed during the deprotection with residual water present in the solvent. The isolation of the formed trityl- methanol from the solvent thereby serves two purposes.

First of all, it helps the purification of the desired de- protected compound of formula (I) and second it provides a source of trityl-methanol . The so obtained trityl-methanol can be used again e.g. in the synthesis of the trityl-protected compounds of formula (II), saving resources and thus making the process more economical as well as more environmentally friendly.

Precipitation is a particularly preferred method for isolating the formed trityl-methanol since it can be effected by simply cooling the reaction mixture without the need for more complex

purification techniques such as extractions or column chromatography.

In a further embodiment of the invention, the compound of formula (II) is reacted with the compound of formula (III) at a temperature from 50 to 70 ⁰ C, preferably from 55 to 65 ⁰ C.

When deprotecting larger and potentially unstable organic compounds such as those of formula (II), a balance must be found between the fact that at higher temperatures these compounds have the tendency to degrade, resulting in a lower yield, and the necessity that the temperature is high enough so that the deprotection reaction proceeds within a reasonable period of time .

It has been found that in the above-named temperature ranges, the reactions can be performed in 1 to 4 hours while obtaining a good yield.

In a further embodiment of the invention, the compound of formula (II) is reacted with the compound of formula (III) for 1.5 to 4.5 hours, preferably for 2.0 to 3.5 hours.

Since the deprotection reaction involves heating a larger organic compound in the presence of a reactive agent, a longer reaction time is always connected with the risk of degrading large amounts of the starting or the target compound. Too short a reaction time on the other hand will result in an incomplete deprotection .

It has been found that in the above-named time ranges a virtually complete deprotection can be achieved while only small quantities of the desired compound are degraded, leading to good 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 in any way.

General Procedure for the Deprotection of Trityl-Protected Biphenyl-Tetrazole Compounds

A trityl-protected biphenyl-tetrazole compound of formula (II) is heated together with a compound of formula (III) in a solvent at 50 to 70 ⁰ C while stirring. The progression of the reaction is monitored by HPLC. After most of the starting compound of formula (II) is consumed, usually after 1.5 to 4.5 hours, the stirring is stopped and the solution is further aged at the same temperature . The pH of the solution is raised by the addition of base to a value of 3.5 to 5.0. The solution is cooled to 0 to 5 ⁰ C and stirred, while trityl-methanol precipitates from the solution. The resulting suspension is filtered and the precipitated trityl-methanol is washed with more cold solvent and can be used again in the synthesis of trityl- protected compounds . The solvent and free hydroxylammonium compounds are removed from the filtrate under reduced pressure in order to obtain the crude compound of formula ( I ) . The so obtained crude product can then be further processed, for example by recristallization.

EXAMPLE 1

Preparation of Losartan from Tritvl-Protected Losartan

Trityl-Protected Losartan Losartan

A 6 1 3-necked flask equipped with a reflux condenser was charged with 3 1 methanol, 600 g trityl-protected Losartan and

144 g hydroxylammonium chloride. The mixture was heated to 60 ⁰ C and stirred for 2 hours at this temperature. At the end of the 2 hours, a turbid yellowish solution was obtained. This solution was analyzed by HPLC. The analysis indicated that 99.5 % of the trityl-protected Losartan had been consumed. The solution was aged for another half an hour at 60 ⁰ C as slightly yellowish crystals started to precipitate. The pH of the mixture was measured as 2.95. The reaction mixture was cooled down to 40 ⁰ C and 35 ml triethylamine were added to bring the pH to 3.6. The mixture was cooled to 4 ⁰ C and stirred at 0 to 5 ⁰ C for 1 hour .

The resulting slurry was filtered and the filter cake containing precipitated trityl-methanol was washed with 50 ml cold methanol and sucked to dryness. 210 g wet trityl-methanol were recovered.

The methanol was removed from the filtrate under reduced pressure. 900 ml ethyl acetate were added to the obtained residue and the mixture was stirred for 1 hour at 5 to 10 ⁰ C. A homogeneous precipitate was obtained, filtered and washed with 100 ml cold ethyl acetate.

498 g of colorless needles of Losartan were obtained which were dried at 60 ⁰ C under vacuum to yield 364 g of a white powder (94.7 % yield) .

EXAMPLE 2

Preparation of Losartan from Trityl-Protected Losartan

A l l 3-necked flask equipped with a thermometer and a reflux condenser was charged with 400 ml isopropanol and 60 g trityl- protected Losartan. The suspension was heated to 60 ⁰ C at which point 27.1 g hydroxylammonium sulfate were added and the mixture was stirred at 60 to 65 ⁰ C for 3.5 hours. Towards the end of the reaction period a turbid solution was obtained. A HPLC analysis indicated that 99.2 % of the trityl-protected Losartan had been consumed. The reaction mixture was stirred at 60 to 65 ⁰ C for an additional half an hour and then cooled to room temperature. The pH of the mixture was measured as 2.4 and 4.5 ml of triethylamine were added to bring the pH to 3.5. Meanwhile, colorless crystals of trityl-methanol started to precipitate. The obtained suspension was cooled to 0 to 5 ⁰ C and stirred at this temperature for 2 more hours .

The obtained suspension was filtered and the precipitated trityl-methanol was washed with 20 ml cold isopropanol. 21.6 g of wet trityl-methanol were recovered.

The isopropanol was removed from the filtrate under reduced pressure. 95 ml ethyl acetate were added to the obtained residue and the resulting suspension was stirred for 1 hour at 5 to 10 ⁰ C.

The obtained homogeneous precipitate in ethyl acetate was filtered and washed with 10 ml cold ethyl acetate. 49.2 g of colorless crystals of wet Losartan were obtained which were dried at 60 ⁰ C under vacuum to yield 36 g of a powder (93.8 % yield).

EXAMPLE 3

Preparation of Irbesartan from Trityl-Protected Irbesartan

Trityl-Protected Irbesartan Irbesartan

A reaction vessel equipped with a reflux condenser was charged with 3 1 methanol and 138 g hydroxylammonium chloride. The mixture was stirred at room temperature for half an hour and then heated at 40 °C for a further half hour. To this solution, 600 g trityl-protected Irbesartan were added in portions. After all trityl-protected Irbesartan had been added, the reaction mixture was heated to 60 to 65 ⁰ C and stirred for 2 hours at this temperature. The obtained slightly yellow solution was analyzed by HPLC and it was found that 99.4 % of the trityl- protected Irbesartan had been consumed. The mixture was cooled to 40 ⁰ C. The pH of the solution was measured as 3.1 and 42 ml of triethylamine were added to bring the pH to 4.55. The reaction mixture was cooled to 0 ⁰ C and stirred for 1 hour to precipitate the formed trityl methanol resulting in a slurry.

The slurry was filtered and the obtained filter cake was sucked to dryness and washed with 100 ml cold methanol.

The methanol was removed from the filtrate under reduced pressure. 1.2 1 ethyl acetate were added to the obtained residue and the resulting slurry was aged under agitation for 3 hours at room temperature followed by a filtration. 590 g wet Irbe- sartan were recovered and dried at 60 ⁰ C to constant weight to yield 260 g dry Irbesartan (67.8 % yield).