Intermediate compounds for the preparation of angiotensin II antagonists

Field of the invention

The present invention relates to novel substituted biphenyltetrazole compounds useful as intermediates in the preparation of angiotensin II antagonists, to a process for the synthesis of them and to a process for the conversion thereof to said molecules.

Background of the invention

Angiotensin II antagonists are useful as therapeutics for hypertension, circulatory diseases, such as heart failure, strokes, cerebral apoplexy, nephropathy, nephritis, glaucoma, anxiety and inflammatory disorders.

Most of said angiotensin II antagonists have a common biphenyltetrazole moiety and can be represented by the following Formula (I)

(I)

wherein A is an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue.

More particularly, the substituent A in compounds of Formula (I) can have the following meanings, which identify specific angiotensin II antagonists: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l -yl (losartan); (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoylamino (valsartan); 2-butyl- 1 ,3-diaza-spiro[4,4]non- 1 -en-4-on-3-yl (irbesartan); 2-ethoxy-3H-benzimidazole-4-carboxylic acid (candesartan);

2-ethoxy-3H-benzimidazole-4-(l-cyclohexyloxycarbonyloxyet hyl)carboxylate (candesartan cilexetil);

5-carboxy-4-(l-hydroxy-l-methylethyl)-2-proρy-imidazo-l- yl (olmesartan);

5-((5-methyl-2-oxo-l ,3-dioxol-4-yl)methylcarboxylate)-4-( 1 -hydroxy- 1 -methylethyl)-2- propy-imidazo-1-yl (olmesartan medoxomil).

The compounds of Formula (I) contain a tetrazolyl group, in which a reactive nitrogen atom is present. It is known that the reactive tetrazole nitrogen in compounds of Formula (I) can be protected with a protecting group.

Generally speaking, a protecting group is a group which blocks a reactive site in a compound having more than one reactive group, so that the chemical reaction can be carried out selectively on another unprotected reactive site, said protecting group being easily removed at the end of the selective reaction.

Among the processes described in literature for the preparation of compounds of Formula

(I) the preferred protecting group of the reactive nitrogen atom of the tetrazolyl ring is the triphenylmethyl (trityl) group.

A number of processes for the preparation of compounds of Formula (I) disclose the reaction between a compound of Formula (II),

⁽ ID ¹

wherein X is a leaving group, and a suitable nucleophilic reagent A-H, wherein A has the meaning as indicated above, in presence of a base to obtain, after removing the trityl protecting group, a compound of Formula (I).

According to EP 291 969, losartan was prepared by reaction of 4'-methyl-biphenyl-2- carbonitrile with trialkyltin azide, to give the compound of Formula (III):

(HI)

The protection of the tetrazole ring of the compound of Formula (III) with triphenylmethyl chloride followed by radical bromination gave compound of Formula (II), wherein X is Br. The reaction of said compound of Formula (II) with 2-butyl-4-chloro-5-formylimidazole in presence of sodium ethoxide, followed by reduction with sodium borohydride of the formaldehyde moiety on imidazole to hydroxymethyl, gave a compound than could be converted to losartan, after removal of the trityl protecting group.

According to WO 2004101534, valsartan was prepared by reaction of the compound of Formula (II), wherein X is Br, with L-valine benzyl ester in presence of ethyl diisopropyl amine as a base and conversion to valsartan, via a reaction with valeryl chloride and removal of the trityl protecting group. According to WO 2004072064, irbesartan was prepared by reaction of the compound of Formula (II), wherein X is Br, with l-(N'-pentanoylamino)cyclopentanecarboxylic acid amide in the presence of an inorganic base to give a compound than can be converted to irbesartan after removal of the trityl protecting group.

Candesartan, candesartan cilexetil, olmesartan and olmesartan medoxomil can be obtained analogously.

Removal of the trityl protecting group is traditionally carried out in the presence of strong inorganic or organic acids, such as hydrochloric, methanesulfonic, toluenesulfonic, trifluoroacetic, trifluoromethanesulfonic, sulfuric (Russian Journal of Organic Chemistry (translation of Zhurnal Organicheskoi Khimii), 36(5), 740-742, 2000), perchloric, or other strong acids; or in the presence of strong bases, such as potassium hydroxide. In WO 2005049586 the trityl protective group is removed from valsartan by a hydrogen chloride solution in 1,3-dioxane. WO 2005037821 encompasses the preparation of candesartan cilexetil by the deprotection of the trityl candesartan cilexetil using one organic solvent (MeOH, heated to reflux temperature) and/or one organic acid (formic acid, methanesulfonic acid, p-toluene sulphonic acid) at room temperature. EP 668272 discloses a process where the trityl protective group is removed from N- protected tetrazolyl compounds (e.g. candesartan cilexetil) by reacting them with a mineral acid (e.g., HCl, H ₂ SO ₄ ) under substantially anhydrous conditions in the presence of an alcohol (e.g. MeOH, EtOH).

WO 2002094816 and EP 1274702 describe a process where the trityl protective group is removed from losartan with potassium hydroxide under reflux temperature of an alcohol. The removal of the triphenylmethyl group include the use of strongly corrosive acids or the use of strong bases. When the tetrazolyl compound contains a group that can be cleaved in these conditions, this technology cannot be utilized. Furthermore, the cleavage of the triphenylmethyl group requires the removal of the formed trityl alcohol from the reaction mixture by filtration, chromatography, crystallization, centrifugation, etc. An object of the present invention is to provide novel compounds useful as intermediates in the preparation of angiotensin II antagonists, process for the synthesis of them and process for the conversion thereof to said molecules, that avoid the above-mentioned disadvantages.

Summary of the invention

We have found that the reactive tetrazole nitrogen in a biphenyltetrazole compound can be efficiently protected with the 2-(trimethylsilyl)ethoxymethyl (SEM) group to give the compounds of Formula (IV)

(IV)

wherein: X is selected from H; or a leaving group: Cl; Br; I; F; OH; O-tosyl; O-mesyl.

In a first aspect, the invention provides compounds of Formula (IV), wherein X is as defined above.

In a further aspect, the invention provides compound of Formula (V)

(V)

wherein:

A is selected from an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue; as well as its geometrical isomers, its tautomers, its optically active forms as enantiomers, diastereomers and its racemate forms.

In a further aspect, the invention provides the use of a compound of Formula (IV) and Formula (V), as intermediates for the preparation of angiotensin II antagonists of Formula (I), or a pharmaceutically acceptable salts thereof,

(I)

wherein A is selected from an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue.

In a further aspect, the invention provides a method of synthesis of a compound according to Formula (IV) and Formula (V).

In a further aspect, the invention provides a process for the deprotection of the reactive tetrazole nitrogen in a compound containing a SEM group, comprising the reaction of the

protected compound with MHSO ₄ -SiO ₂ , wherein M is an alkali metal. A compound containing a SEM group is preferably a compound of Formula (V).

In a further aspect, the invention provides a process for the preparation of compounds of Formula (I) or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly through- out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

"Alkyl" refers to monovalent straight or branched C ₁ -C ₁₂ alkyl groups, in particular C ₁ -Ce alkyl. This term is exemplified by groups such as methyl, ethyl, w-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, n-hexyl, heptyl, octyl, nonyl, decanoyl, undecanoyl, dodecanoyl and the like.

"Heterocycle" refers to a saturated, unsaturated and aromatic carbocyclic group having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl, bicyclic or a tricyclic fused-ring) or spiro, in which 1 to 3 carbon atoms are replaced by hetero atoms chosen from the group consisting of O, S, ^' rVR, R being defined as hydrogen or alkyl. Particular examples of heterocycle groups include optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, 1-methylpiperazinyl, morpholino, pyridyl, pyrrolyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4- triazinyl, 1,2,3-triazinyl, benzotriazolyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, imidazo-thiazolyl, imidazo-triazinyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-

b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, pyrido-oxazinyl, piperidino[2,3- </]pyrimidinyl, diazabenzimidazolyl, pyrazino-pyridazinyl, pyrazolo-oxazolyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl or 1,3-diazaspiro and the like.

"Open amide residue" refers to an amide group in which the nitrogen atom can be substituted with the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle or aryl.

"Amino residue" refers to the group -NRR' where each R, R' is independently hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle or aryl.

"Substituted": unless otherwise constrained by the definition of the individual substituent, i the above set out groups, like "alkyl", "alkenyl", "alkynyl", "cycloalkyl", "aryl", "heterocycle", "open amide residue", "amino residue", etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, halogen, amino, aminosulfonyl, ammonium, aminocarbonyl, imide, amidine, imine, sulfinyl, sulfanyl, sulfonyl, hydroxy, alkoxy, alkoxycarbonyl, formyl, ketone, acyl, acyloxy, acylamino, carboxylic acid, carbamate, trihalomethyl, cyano, mercapto, nitrile, isonitrile, nitro, ureido and the like. Alternatively, said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.

We have found that the reactive tetrazole nitrogen in a biphenyltetrazole compound can be efficiently protected with the SEM group to give the compounds of Formula (IV) and (V), useful as intermediates in the preparation of angiotensin II antagonists.

In an embodiment, the invention provides compounds of Formula (IV)

(IV) wherein:

X is selected from H; or a leaving group: Cl; Br; I; F; OH; O-tosyl; O-mesyl. X is preferably H, Br.

A further aspect of the invention is a process for the preparation of a compound of Formula (IV) comprising the protection of the reactive tetrazole nitrogen with the SEM protective group. The SEM protective group was attached with high yield by reaction of the tetrazole compound with the commercially available 2-(trimethylsilyl)ethoxymethyl chloride (SEM- Cl) in a suitable inert solvent in the presence of organic or inorganic bases.

In another embodiment, the invention provides compounds of Formula (V)

(V)

wherein:

A is selected from an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue; as well as its geometrical isomers, its tautomers, its optically active forms as enantiomers, diastereomers and its racemate forms.

In compounds of Formula (V), A is preferably:

2-butyl-4-chloro-5-hydroxymethyl-imidazol- 1 -yl; N-(l-alkylcarboxylate-2-methylprop-l-yl)amino, preferably N-(I -methy lcarboxylate-2- methylprop-l-yl)amino or N-(I -ethyl carboxylate-2-methylprop-l-yl)amino, or N-(I- benzylcarboxylate-2-methylprop-l-yl)amino;

(S)-N-(I -alkylcarboxylate-2-methylprop-l-yl)-N-pentanoylamino, preferably (S)-N-(I- methylcarboxylate-2-methylprop-l -yl)-N-pentanoylamino or (S)-N-(I -ethylcarboxylate-2- methylprop-l-yl)-N-pentanoylamino, or (S)-N-(I -benzylcarboxylate-2-methylprop-l-yl)-

N-pentanoylamino ;

2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl; alkyl 2-amino-3-nitrobenzoate, preferably methyl 2-amino-3-nitrobenzoate or ethyl 2- amino-3 -nitrobenzoate; 2-ethoxy-3H-benzimidazole-4-alkylcarboxylate, preferably 2-ethoxy-3H-benzimidazole-4- methylcarboxylate or 2-ethoxy-3H-benzimidazole-4-ethylcarboxylate;

2-ethoxy-3H-benzimidazole-4-carboxylic acid;

2-ethoxy-3H-benzimidazole-4-(l-cyclohexyloxycarbonyloxyet hyl)carboxylate;

5-alkylcarboxylate-4-(l -hydroxy- 1 -methylethyl)-2-propy-imidazo- 1 -yl, preferably 5- methy lcarboxy late-4-( 1 -hydroxy- 1 -methy lethyl)-2-propy-imidazo- 1 -yl or 5 - ethylcarboxylate-4-(l -hydroxy- 1 -methylethyl)-2-propy-imidazo- 1 -yl;

5-carboxy-4-(l -hydroxy- 1 -methy lethyl)-2-propy-imidazo-l -yl;

5-((5-methyl-2-oxo-l,3-dioxol-4-yl)methylcarboxylate)-4-( l-hydroxy-l-methylethyl)-2- propy-imidazo- 1 -yl.

The invention provides the use of a compound of Formula (IV) and Formula (V), for the preparation of a compound of Formula (I)

(I)

wherein:

A is an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or a pharmaceutically acceptable salts thereof.

In compounds of Formula (I), A is preferably: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl;

(S)-N-( 1 -carboxy-2-methylprop- 1 -yl)-N-pentanoylamino;

2-butyl- 1 ,3 -diaza-spiro [4,4]non- 1 -en-4-on-3 -yk

2-ethoxy-3H-benzimidazole-4-carboxylic acid;

2-ethoxy-3H-benzimidazole-4-(l-cyclohexyloxycarbonyloxyet hyl)carboxylate; 5 -carboxy-4-( 1 -hydroxy- 1 -methylethyl)-2-propy-imidazo- 1 -y 1;

5-((5-methyl-2-oxo- 1 ,3 -dioxol-4-yl)methylcarboxylate)-4-(l -hydroxy- 1 -methylethyl)-2- propy-imidazo- 1 -yl.

In another embodiment, the invention provides a process for the preparation of a compound of Formula (I) ₅ or a pharmaceutically acceptable salts thereof, which comprises: a) reacting a compound of Formula (IV), wfoerein X is a leaving group as defined above, with a suitable nucleophilic reagent A-H, wherein A is: an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue; in the presence of a base to give a compound of Formula (V), wherein A is: an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue;

( I V) (V)

The appropriate nucleophilic reagent A-H is selected from the reagents comprising: 2-butyl-4-chloro-5-formyl-imidazole;

L-valine alkyl ester, preferably L-valine methyl ester or L-valine ethyl ester, or L-valine benzyl ester;

2-n-butyl- 1 ,3 -diaza-spiro [4,4]non- 1 -en-4-one ;

2-propyl-5-[( 1 -hydroxy- 1 -methyl)ethyl]- 1 H-imidazol-4-alkylcarboxylate, preferably 2- proρyl-5-[(l-hydroxy-l-methyl)ethyl]-lH-imidazol-4-methylca rboxylate or 2-propyl-5-

[( 1 -hydroxy- 1 -methyl)ethyl]- 1 H-imidazol-4-ethylcarboxylate;

N-protected alkyl 2-amino-3-nitrobenzoate, preferably N-protected methyl 2-amino-3- nitrobenzoate or N-protected ethyl 2-amino-3-nitrobenzoate;

2-ethoxy-3H-benzimidazole-4-alkylcarboxylate, preferably 2-ethoxy-3H- benzimidazole-4-methylcarboxylate or 2-ethoxy-3H-benzimidazole-4-ethylcarboxylate. b) when A in the compound of Formula (V) is an optionally protected amino residue: conversion by cyclization of the said optionally protected amino residue in an optionally substituted heterocycle, containing at least one nitrogen atom; or conversion by reaction with an organic acyl derivative of the said optionally protected amino residue in an open amide residue; obtaining the compound of Formula (V), wherein A is: an optionally substituted heterocycle, containing at least one nitrogen atom; . or an open amide residue; c) removing the SEM protecting group in a compound of Formula (V), wherein A is: an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue.

( V) ( I )

It is known that the removal of the SEM group man be carried out as described in Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3 ^rd Edition 1999, for instance by hydrolysis with HCl in an alcohol, such as ethanol, o TBAF in an ether, such as tetrahydrofuran.

Now, we have found that the deprotection of the reactive tetrazole nitrogen can be easily obtained with high yield with MHSO ₄ -SiO ₂ , wherein M is an alkali metal, selected from the

group consisting of Na or K, preferably Na, in at least one organic solvent, thereby making possible its application to N-protected tetrazolyl compounds having a moiety liable to be cleaved by acid hydrolysis. Although the N-protected tetrazolyl compound that can be used in this invention is virtually not limited, the invention is particularly useful when the starting N-protected tetrazolyl compound has at least one hydrolizable group other than the protective group of the N-protected tetrazolyl compound.

The removing of the SEM protecting group (step c) of the above process in a compound of Formula (V), wherein A is: an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; is accomplished with an acid, preferably HCl, or TBAF or MHSO ₄ -SiO ₂ , wherein M is an alkali metal, preferably NaHSO ₄ -SiO ₂ , in at least one organic solvent, preferably EtOH, acetone, THF, CH ₂ Cl ₂ MeOH or CH ₂ Cl ₂ ZEtOH.

A process for the preparation of losartan, valsartan, irbesartan, candesartan, candesartan cilexetil, olmesartan or olmesartan medoxomil is provided.

Synthesis of compounds of the invention

The following abbreviations refer respectively to the definitions below: AcOH (acetic acid), AcOEt (ethyl acetate), DIEA (diisopropyl ethylamine), DMF (dimethyl formamide), NBS (N-bromo succinimide), TEA (triethylamine), THF (tetrahydrofuran), TBAF (tetra-π-butylammonium fluoride), TLC (thin layer chromatography).

The compounds according to Formula (IV) and Formula (V), as well as its tautomers, its geometrical isomers, its optically active forms such as enantiomers, diastereomers and racemate forms thereof, are novel compounds.

The compounds according to Formula (IV) and Formula (V), exemplified in this invention, may be prepared from readily available starting materials, such as 5-[2-(4'- methylbiphenylyl)]tetrazole (III) by several synthetic approaches. Examples of synthetic pathways for compounds derivatives according to Formula (IV) and Formula (V), will be described. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. According to a further general process, compounds of Formula (IV) and Formula (V), can be converted to alternative compounds of Formula (IV) and Formula (V), employing suitable interconversion techniques well known by a person skilled in the art. If the above set of general synthetic methods is not applicable to obtain compounds according to Formula (IV) and Formula (V), and/or necessary intermediates for the synthesis of compounds of Formula (IV) and Formula (V), suitable methods of preparation known by a person skilled in the art should be used. In general, the synthesis pathways for any individual compound of Formula (IV) and Formula (V) will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3 ^rd Edition 1999.

As previously reported, the compounds of Formula (IV) and Formula (V), are useful as intermediates for the preparation of angiotensin II antagonists. Angiotensin II antagonists can be prepared from compounds of Formula (IV) and Formula (V) according to what

previously described. In the present context the usefulness of the compounds of Formula (IV) and Formula (V) is particularly exemplified in the preparation of compounds known as losartan, valsartan, irbesartan, candesartan, candesartan cilexetil, olmesartan and olmesartan medoxomil.

Depending on the nature of X or A different synthetic strategies may be selected for the synthesis of compounds of Formula (IV) and Formula (V).

Compounds of Formula (IV), wherein X is H (IVa) may be obtained by reaction of the commercially starting material 5-[2-(4'-methylbiphenylyl)]tetrazole (III) with the commercially available SEM-Cl in presence of organic or inorganic bases, such as TEA,

DIEA, pyridine, NaH, sodium alcoholate, such as NaOMe or NaOEt, or any carbonate salts, such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , in at least one organic solvent for a suitable time and at a suitable temperature, preferably room temperature. The solvent or solvents mixture may be selected between an ether, such as THF or dioxane; a chlorinated hydrocarbon, such as dichloromethane or chloroform; an ester, such as ethyl acetate; an hydrocarbon, such as toluene; a ketone, such as acetone; a nitrile, such as acetonitrile; an amide, such as DMF; a sulfoxide, such as dimethylsulfoxide; or a sulfohe, such as dimethylsulfone; etc. The choice of solvent or solvents mixture may depend on the nature of the base. Particularly preferred is TEA in CH ₂ Cl ₂ . The reaction time may easily be determined by monitoring the reaction progress and/or completion by TLC (Scheme 1).

Scheme 1:

SEWCI , Base NBS, per oxi de

( I I I ) ( I Va) ( I Vb)

The protection of the reactive tetrazole nitrogen with the SEM group gave a mixture of two isomers (IVa) in about a 1:2 ratio, characterized by ¹ H-NMR. The two isomers are l-(2- trimethylsilylethoxymethyl)-5 -[2-(4' -methylbiphenylyl)] - 1 H-tetrazole and 2-(2- trimethylsilylethoxymethyl)-5-[2-(4'-methylbiρhenylyl)]-2H- tetrazole, (IVa ₁ ) and (IVa ₂ ). The mixture of the two isomers can be used for the following steps without further purification, as the final step of the different processes is always the removal of the SEM group from the reactive tetrazole nitrogen.

Compounds of Formula (IV), wherein X is Br (IVb) may be prepared by reaction of the two isomers (IVa) with a radical initiator, such as dibenzoyl peroxide, di-tert-butylperoxide, and NBS in a chlorinated hydrocarbon, such as CH ₂ Cl ₂ CCl ₄ (Scheme 1). An example of this conversion is described by L. Horner et al., Angew. Chem, 71, 349, 1959. The mixture of the two isomers can be used for the following steps without further purification.

Compounds of Formula (IV) ₃ wherein X is Cl; I; F; OH; O-tosyl; O-mesyl may be prepared by oxidation or radical halogenation of a compound of Formula (IV), wherein X is H; by reacting a compound of Formula (IV), wherein X is Br, with a nucleophilic reagent; and, if required, converting a product of Formula (IV) into a product of Formula (IV) employing suitable interconversion techniques well known by a person skilled in the art: radical halogenation, nucleophilic reaction, oxidation, displacement, tosylation or mesylation.

Compounds of Formula (V), wherein A is an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue may be prepared by reacting a compound of Formula (IV), wherein X is a leaving group as defined above, with a suitable nucleophilic reagent A-H, wherein A is an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue; or an optionally protected amino residue; in the presence of a base. If required, compounds of Formula (V) can be converted into a product of Formula (V) employing

suitable interconversion techniques well known by a person skilled in the art: reduction, hydrolysis, hydrogenation, esterification, conversion by cyclization of an optionally amino residue into an optionally substituted heterocycle, containing at least one nitrogen atom; conversion by reaction of an optionally protected amino residue with an organic acyl derivative, such as an acyl chloride or an ester, pito an open amide residue.

Compounds of Formula (I), may be prepared by removing the SEM protecting group in a compound of Formula (V), wherein A is an optionally substituted heterocycle, containing at least one nitrogen atom; or an open amide residue with an acid such as, for instance, HCl, or TBAF in at least one organic solvent. Preferably, the reaction is carried out in EtOH, or THF or acetone.

The removal of the SEM group from the N-protected tetrazolyl compound of Formula (V) can be efficiently carried out with MHSO ₄ -SiO ₂ , wherein M is an alkali metal, selected from the group consisting of Na or K, preferably Na, in at least one organic solvent for a suitable time and at a suitable temperature.

The organic solvents are selected from an alcohol, such as methanol or ethanol; a ketone, such as acetone; an ether, such as THF or dioxane; a chlorinated hydrocarbon, such as dichloromethane or chloroform; an ester, such as ethyl acetate; an hydrocarbon, such as toluene; a nitrile, such as acetonitrile; an amide, such as N,N-dimethylformamide; a sulfoxide, such as dimethylsulfoxide; or a sulfone, such as dimethylsulfone; or their mixtures. Preferably, the reaction is carried out in CH ₂ Cl ₂ MeOH or CH ₂ Cl ₂ ZEtOH. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent or the solvents mixture. The reaction time may easily be determined by monitoring the reaction progress and/or completion by TLC.

Compounds of Formula (I), wherein A is 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl (Ia) may be prepared as described in US 4,820,843, by displacement of the Br moiety of the

two isomers (IVb) with 2-butyl-4-chloro-5-formyl-imidazole, in presence of a base, such as K ₂ CO ₃ , in DMF, and following reduction with NaBH ₄ in water and an aqueous solution of NaOH (10%) to give the compound (Va). The removal of the SEM group can be carried out from the compound (Va) by hydrolysis with HCl IN or TBAF in EtOH, to give the compound (Ia), without the need of further purification (Scheme 2).

Scheme 2:

( I Vb) ( Va)

( I a)

Compounds of Formula (I), wherein A is (S)-N-(I -carboxy-2-methylprop-l-yl)-N- pentanoylamino (Ic) may be prepared by reaction of the two isomers (IVb) with a

derivative of L-valine, L-valine benzyl ester or L-valine alkyl ester, such as L-valine methyl ester in presence of a base, such as K ₂ CO ₃ in AcOEt, and following reaction with valeryl chloride to give the open amide residue of the compound (Vb). An example of this conversion is described in EP 1556363. The removal of the SEM group can be carried by heating the compound (Vb) with HCl 2N in EtOH, to give the compound (Ib), that was straight transformed in the final compound (Ic) ^x by hydrolysis with NaOH in water (Scheme 3) or by hydrogenation over a catalyst, such as Pd/C.

Scheme 3:

( I Vb) ( Vb)

( I b)

Compounds of Formula (I), wherein A is 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl (Id) may be prepared by reaction of the two isomers (IVb) with 2-n-butyl-l,3-diaza- spiro[4,4]non-l-en-4-one, in presence of a base, such as NaH in DMF to give the compound (Vc). An example of this conversion is described in US 5,270,317. The removal of the SEM group can be carried out by heating the compound (Vc) with HCl IN in EtOH or THF or acetone to give the compound (Id), without the need of further purification (Scheme 4).

Scheme 4:

( I Vb) ( Vc)

( I d)

Compounds of Formula (I), wherein A is 5-((5-methyl-2-oxo-l,3-dioxol-4- yl)methylcarboxylate)-4-(l -hydroxy- l-methylethyl)-2-propyl-imidazo-l-yl (Ie) may be prepared by reaction of the two isomers (IVb) with 2-propyl-5-[(l -hydroxy- 1- methyl)ethyl]-3H-imidazole-4-alkylcarboxylate, such as 2-propyl-5-[(l -hydroxy- 1- methyl)ethyl]-3H-imidazole-4-ethylcarboxylate, in presence of a base, such as K ₂ CO ₃ in DMF, to give the compound (Vd). An analogous example of this conversion is described in WQ 2006029056. The hydrolysis of compound (Vd) with NaOH in THF and water, gave the acid (Ve) that was straight esterified with 4-bromomethyl-5-methyl-l,3-dioxol-2-one, in DMF and K ₂ CO ₃ to give the compound (Vf), without the need of further purification. 4- Bromomethyl-5-methyl-l,3-dioxol-2-one was obtained from 4,5-dimethyl-l,3-dioxol-2- one, NBS, benzoyl peroxide in CCl ₄ , as described in J. Med. Chem., 29(4), 448-453, 1986. Our attempts to carry out the removal of the SEM group from the compound (Vf) whether with HCl at reflux of EtOH, THF or acetone, or with TBAF in THF at room temperature were disappointing. In particular, we obtained only the unwanted hydrolysis of the 5-((5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methylcarboxylate group.

We have found that the removal of the SEM group from the N-protected tetrazolyl compound of Formula (V) can be carried out with MHSO ₄ -SiO ₂ , wherein M is an alkali metal, selected from the group consisting of Na or K, preferably Na, in at least one organic solvent for a suitable time and at a suitable temperature.

The object tetrazolyl compound can be obtained even when the starting N-protected tetrazolyl compound contains a moiety liable to be cleaved by acid hydrolysis. Typically, the new deprotection step comprises the stirring at 50°C for 10 hrs of the compound (Vf) with NaHSO ₄ -SiO ₂ in CH ₂ Cl ₂ /Me0H 9:1 to give compound (Ie) (Scheme 5).

Scheme 5:

SEM

(I Vb) (Vd)

(Ve) (Vf )

( I e)

Compounds of Formula (I), wherein A is 2-ethoxy-3H-benzimidazole-4-carboxylic acid (If) may be prepared by reaction of the _, two isomers (IVb) with 2-ethoxy-3H- benzimidazole-4-alkylcarboxylate, such as 2-ethoxy-3H-benzimidazole-4-ethylcarboxylate (IX), in presence of a base, such as K ₂ Cθ ₃ , in DMF, to give the compound (Vg) and

following hydrolysis with NaOH to give the compound (Vh). An analogous example of this conversion is described in WO2006015134. The removal of the SEM group can be carried out from compound (Vh) by reaction with TBAF in an ether, such as THF, to give the compound (If), without the need of further purification (Scheme 6).

Scheme 6:

( I Vb) ( Vg)

( Vh) ( i f )

The compound (IX) was obtained by deprotection of alkyl 2-[(te/*/-butoxycarbonyl)amino]- 3-nitrobenzoate, such as ethyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (VI) with HCl in MeOH-AcOEt to give 2-amino-3-nitro-benzoic acid ethyl ester (VII).

The reduction of compound (VII) with H ₂ and a catalyst, such as Pd/C, gave compound (VIII), that was cyclized by reaction with tetraethylorthocarbonate in AcOH, yielding the desidered compound (IX) as described in WO2006015134 (Scheme 7).

Scheme 7:

COOEt COOEt

( Vl ) ( VI I )

The compounds of Formula (IV) and (V) object of the present invention are particularly advantageous from the industrial point of view. Particularly, the SEM group is a very good protecting group for the reactive tetrazole nitrogen. It is easy to put on, easy to remove and in high yielding reactions, and inert to the conditions of the reaction required to prepare angiotensin II antagonists.

The use of the SEM group as a protecting group allows its removal without any purification. When the SEM group is removed from compounds of Formula (V), the byproducts of the reaction are removed during the usual work-up of the reaction, without any further purification processes, such as titration, chromatography, crystallization,

centrifugation, etc. The use of the SEM group as a protecting group allows compounds of Formula (I) to be obtained by deprotection of the SEM group without any further purification. The SEM protecting group is easily removed with high yield in conditions that are compatible with liable functional groups. This represents a further advantage for the industrial production.

Compounds of this invention can be isolated, alone or in association with solvent molecules, by crystallization or by evaporation of an appropriate solvent.

In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.

Example 1: N-(2-Trimethylsilylethoxymethyl)-5-[2-(4'-methylbiphenylyI)] -tetrazoIe (IVa)

To a solution of 5-[2-(4'-methylbiphenylyl)]tetrazole (III) (7.28 g, 0.0308 mol) in CH ₂ Cl ₂ (100 mL) were added TEA (4.71 mL, 0.0339 mol) and SEM-Cl (6 mL, 0.0339 mol), at 0°C, under N ₂ atmosphere. The solution was kept at 0°C for 5', than stirred at room temperature for 2 hrs (TLC monitoring: CH ₂ Cl ₂ /Me0H 9:1). The solution was washed with water, with a saturated solution OfNa ₂ CO ₃ and finally with water. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a mixture of two isomers of compound (IVa) (10.98 g) as an oil.

The two isomers are: l-(2-trimethylsilylethoxymethyl)-5-[2-(4'-methylbiphenylyl)] -lH- tetrazole and 2-(2-trimethylsilylethoxymethyl)-5-[2-(4'-methylbiphenylyl)] -2H-tetrazole, (IVai) and (IVa ₂ ), in about a 1 :2 ratio. The mixture of two isomers (IVaO and (IVa ₂ ) was used without further purification for the following steps. Yield: 97.3%

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.1 (s, 9H ₀ V _a2) , Me ₃ Si), -0.02 (s, 9H _(IVa i ₎ , Me ₃ Si), 0.67 (t, J=8.4Hz, 2H _(1Va2) , OCH ₂ CH ₂ Si), 0.89 (t, J=8.2ηz, 2H _(1Va i), OCU ₂ CH ₂ Si), 2.31 (s, 3H _(IVa2 > ArCH ₃ ), 2.33 (s, 3H _(IVa o, ArCH ₃ ), 3.32 (t, J=8.4Hz, 2H ₍ i _Va2 ), OCH ₂ CH ₂ Si), 3.58 (t, J=8.2Hz, 2H _(IVa ,), OCH ₂ CH ₂ Si), 5.00 (s, 2H _(IVa2) , OCH ₂ N), 5.78 (s, 2H _(IVa i ₎ , OCH ₂ N), 7.00- 7.02 (m, 2H _(IVa2 )), 7.07-7.09 (m, 4H ₍ i _Va i) + 2H(W ₈₂ )), 7.44-7.59 (m, 3H _(IV a.) + 3H _αVa 2)) 7.62- 7.66 (m, IH(IVa ₂ )), 7.80-7.83 (m, lH( _1Va i)) (aromatic protons) ppm.

Example 2: N-(2-Trimethylsilylethoxymethyl)-5-[2-(4'-bromomethylbipheny lyl)]-tetrazole (IVb)

To a solution of the two isomers (IVa) (13 g, 0.03552 mol) in CCl ₄ (250 mL), were added dibenzoyl peroxide (0.25 g, 0.001032 mol) and NBS (6.32 g, 0.03551 mol) at room temperature. The mixture was stirred at 77°C for 20 hrs (TLC monitoring: CH ₂ Cl ₂ ). The mixture was washed with a saturated solution Of NaHCO ₃ , then with water. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a mixture of two isomers of compound (IVb) (16.22 g) as an orange oil, that was used for the following steps without further purification.

The two isomers were characterized by ¹ H-NMR after a flash chromatography on silica (CHCl ₃ 100%).

(IVb ₁ ) (isomer with lower elution time):

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.01 (s, 9H ₅ Me ₃ Si), 0.91 (t, J=7.8Hz, 2H, OCH ₂ CH ₂ Si), 3.61 (t, J=7.8ηz, 2H, OCH ₂ CH ₂ Si), 4.50 (s, 2H, CH ₂ Br), 5.77 (s, 2H, OCH ₂ N) ₅ 7.16-7.18 (m, 2H) 7.31-7.33 (m, 2H) 7.44-7.57 (m, 3H) 7.88 (m, IH) (aromatic protons) ppm.

(IVb ₂ ) (isomer with higher elution time):

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.09 (s, 9H, Me ₃ Si), 0.70 (t, J=8.4Hz, 2H, OCH ₂ CH ₂ Si), 3.37 (t, J=8.4ηz, 2H, OCH ₂ CH ₂ Si), 4.44 (s, 2H, CH ₂ Br), 5.06 (s, 2H, OCH ₂ N), 7.11-7.13 (m, 2H) 7.30-7.32 (m, 2H) 7.50-7.60 (m, 3H) 7.65-7.69 (m, IH) (aromatic protons) ppm.

Example 3:

[2-Butyl-5-chloro-3-[[4-[2-(2H-tetrazoI-5-yl)phenyl]pheny l]methyl]-3H-imidazol-4- yl] methanol (Iosartan) (Ia)

Step I: [2-Butyl-5-chloro-3-[[4-[2-(N-(2-trimethylsilylethoxymethyl) tetrazol-5-yl)phenyl] phenyl] methyl] -3H-imidazol-4-yl] methanol (Vέ)

The two isomers (IVb) (1 g, 0.002245 mol), K ₂ CO ₃ (0.372 g, 0.002694 mol) and 2-butyl-4- chloro-5-formyl-imidazole (0.416 g, 0.002245 mol) were dissolved in DMF (7 mL), at room temperature, under N ₂ atmosphere. The mixture was stirred at room temperature for 22 hrs (TLC monitoring: cyclohexane/AcOEt 8:2).

NaBH ₄ (0.05 g, 0.001322 mol), water (0.184 mL) and an aqueous solution of NaOH (10%) (0.01 mL) were added to the mixture. After 5 hrs, water (25 mL) was added and the mixture was stirred for 30'. The mixture was filtered and the solid was washed with water and dissolved in AcOEt. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a mixture of compound (Va) (0.969 g), that was purified by flash chromatography on silica (cyclohexane/ AcOEt 6:4) to give (Vai) (0.314 g) e (Va ₂ ) (0.164 g) as yellow oils. Yield: 38.5%

(VaO (isomer with lower elution time):

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.02 (s, 9H, Me ₃ Si), 0.89 (t, J=7.4Hz, 3H, CH ₃ (CH ₂ ) ₃ ), 0.90 (t, J=8.2Hz, 2H, SiCH ₂ CH ₂ O), 1.32-1.42 (m, 2H, CH ₂ ), 1.65-1.73 (m, 2H, CH ₂ ), 2.64 (t, J=7.8Hz, 2H, CH ₃ (CHa) ₂ CH ₂ ), 3.64 (t, J=8.2ηz, 2H, SiCH ₂ CH ₂ O), 4.49 (s, 2η,

ArCH ₂ N), 5.23 (s, 2H, CH ₂ OH) ₅ 5.77 (s, 2H, OCH ₂ N), 6.94-6.96 (m, 2H), 7.16-7.18 (m, 2H), 7.36-7.43 (m, IH), 1 Al -1.51 (m, 2H), 7.86-7.91 (m, IH) (aromatic protons) ppm.

(Va ₂ ) (isomer with higher elution time): ¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.08 (s, 9H, Me ₃ Si), 0.72 (t, J=8.4Hz, 2H, SiCH ₂ CH ₂ O), 0.87 (t, J=7.2Hz, 3H, CH ₃ (CH ₂ K), 1.30-1.35 (m, 2H, CH ₂ ), 1.59-1.67 (m, 2H, CH ₂ ), 2.53 (t, J=7.8Hz, 2H, CH ₃ (CH ₂ ) ₂ CH ₂ ), 3.40 (t, J=8.4ηz, 2H, SiCH ₂ CH ₂ O), 4.46 (s, 2H, ArCH ₂ N), 5.08 (s, 2H, CH ₂ OH), 5.19 (s, 2H, OCH ₂ N), 6.92-6.94 (m, 2H), 7.08-7.10 (m, 2H), 7.51- 7.59 (m, 3H), 7.64-7.68 (m, IH) (aromatic protons) ppm.

Step II: P-Butyl-S-chloro-S-f^-^^H-tetrazol-δ-ylJphenylJphenylJmethy lJ-SH-imida∑ol- 4-yl] methanol (losartan) (Ia)

To a solution of compound (Va) (0.1 g, 0.000181 mol) in EtOH (1.8 mL), HCl 1η (1.8 mL) was added. The mixture was stirred at 50°C for 4.5 hrs (TLC monitoring: CHCl ₃ /MeOH 9:1). An aqueous solution of NaOH (10%) was then added until pH 8 was reached. The organic phase was concentrated under reduced pressure to obtain a residue that was dissolved in water. An aqueous solution of HCl IN was added until pH 3 was reached. The precipitated solid was filtered, washed with water and dried under vacuum, to give the compound (Ia) (0.0374 g). Yield: 49%.

¹ H-NMR (400 MHz, CD ₃ OD, δ): 0.88 (t, J=7.2Hz, CH ₃ ), 1.27-1.37 (m, 2H, C(CH ₂ ) ₂ CH ₂ CH ₃ ), 1.50-1.58 (m, 2H, CCH ₂ CH ₂ CH ₂ CH ₃ ), 2.71 (t, J=7.8Hz, 2H, CCH ₂ (CH ₂ ) ₂ CH ₃ ), 4.52(s, 2H, NCH ₂ ), 5.42 (s, 2H, OCH ₃ ), 7.12 (d, J=8.4Hz, 2H) 7.15 (d, J=8.4Hz, 2H) 7.54-7.59 (m, 2H) 7.66-7.70 (m, 2H) (aromatic protons) ppm.

Example 4:

(2S)-3-Methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)pheny l]phenyl]methyI]amino] butanoic acid (valsartan) (Ic)

Step I: (2S) Methyl 3-methyl-2-[pentanoyl-[[4-[2-(N-(2-trimethylsilylethoxymethy l)tetrazol- 5-yl)phenyl]phenyl]methyl]amino]butanoate (Vb)

To a suspension of L-valine methyl ester (0.44 g, 0.003368 mol) and K ₂ CO ₃ (2.48 g, 0.01796 mol) in AcOEt (11 mL), the two isomers (IVb) (1 g, 0.002245 mol) were added, under N ₂ atmosphere. The reaction was stirred at 76°C for 21 hrs (TLC monitoring: v cyclohexane/AcOEt 8:2). Valeryl chloride (0.639 mL, 0.005388 mol) was added at 0°C. After 5 hrs at room temperature, water (15 mL) was added and the mixture was stirred at room temperature for 1 hr. The organic phase was separated, washed with an aqueous saturated solution of NaCl, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 1.53 g of crude (Vb) as a mixture of two isomers, that were purified by flash chromatography on silica (cyclohexane/AcOEt 9:1) to give the compound (Vb) (0.43 g) as a yellow oil. Yield: 34%

M ⁺ (ESI-LC/MS): 579.8

Step II: (2S) Methyl 3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol~5-yl)phenyl]phenyl ]methyl] amino] butanoate (Ib)

HCl 2N (0.5 mL) was added to compound (Vb) (0.1 g, 0.0001724 mol) in EtOH (1 mL). The mixture was heated at 60°C for 4 hrs, then concentrated under reduced pressure to give the compound (Ib) (0.077 g) as a pale yellow solid. Yield: 100%

¹ H-NMR (400 MHz ₅ CD ₃ OD, δ): 0.84-0.87 (m, 3H, CH ₃ ), 0.95-1.01 (m, 3H, CH ₃ ), 1.23- 1.29 (m, 2H, CH ₂ ), 1.39-1.43 (m, 2H, CH ₂ ), 1.53-1.59 (m, 2H, CH ₂ ), 1.67-1.69 (m, 2H, CH ₂ ), 2.21-2.26 (m, IH, CH), 2.33-2.42 (m, 2H, CH ₂ ), 2.50-2.56 (m, IH, CH), 2.65-2.69 (m, IH, CH), 3.30-3.36 (m, COOCH ₃ ), 3.40 (s, COOCH ₃ ), 4.21-4.22 (m, IH, CH) ₅ 4.28- 4.31 (m, IH, CH), 4.66-4.75 (m, 2H, benzyls), 7.03-7.16 (m, 4H, aromatic protons), 7.51- 7.57 (m, 2H, aromatic protons), 7.64-7.69 (m, 2H, aromatic protons) ppm

Step III: {2S)-3-Methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]p henyl]methyl] aminojbutanoic acid (valsartan) (Ic)

Compound (Ib) (0.0771 g, 0.0001717 mol), NaOH (0.04 g, 0.0010302 mol) and water (1 mL) were stirred at room temperature for 20 hrs (TLC monitoring: CH ₂ Cl ₂ /Me0H 95:5). HCl 2N was added until pH 2 was reached. The aqueous solution was extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Ic) (0.070 g). Yield: 93%

¹ H-NMR (400 MHz, CD ₃ OD, δ) of the two rotamers A and B: 0.80 (d, J=6.8Hz, 3H _B , CH ₅ CH), 0.83-0.87 (m, 6H _A , CH ₅ CH ₂ + CH ₃ CH), 0.95 (t, J=7.2Hz, 3H _B , CH ₅ CH ₂ ), 1.00-

1.02 (m, 3H _A +3H _B , CH ₅ CH), 1.23-1.31 (m, 2H _A ), 1.35-1.44 (m, IHA), 1.46-1.59 (m,

1H _A +2H _B ), 1.62-1.69 (m, 2H _B ), 2.16-2.38 (m, 3H _A +1H _B ), 2.47-2.55 (m, 1H _B , CHHCO),

2.61-2.68 (m, 1H _B , CHHCO), 4.14 (d, J=10.4ηz, 1H _B , NCH) ₅ 4.59 (d, J=IOHz, 1H _A ,

NCH), 4.61 (s, 2H _B , NCH ₂ ), 4.67 (d, J=17.4Hz, IH _A , NCHH), 4.77 (d, J=17.4Hz, 1H _A , NCHH), 7.03 (d, J=8ηz, 2H _B ) 7.11 (d, J=8Hz, 2H _A ) 7.19 (d, J=8Hz, 2H _B ) 7.25 (d, J=8Hz,

2H _A ) 7.52-7.58 (m, 2H _A +2H _B ) 7.64-7.69 (m, 2H _A +2H _B ) (aromatic protons) ppm.

Example 5:

2-ButyI-3- [[4- [2-(2H-tetrazol-5-yl)phenylj phenyl] methyl] -1,3-diazaspiro [4.4] non-l-en-

4-one (irbesartan) (Id)

Step I: {2-Bιιtyl-3-[[4-[2-(N-(2-trimethylsilylethoxymethyl)tetraz ol-5-yl)phenyl]phenyl] methyl] -1, 3-diazaspiro[4.4]non-l-en-4-one (Vc)

To a solution of 2-n-butyl-l,3-diaza-spiro[4,4]non-l-en-4-one (1 g, 0.00515 mol) in anhydrous DMF (10 mL), NaH (55-65% in mineral oil, 0.297 g) in anhydrous DMF (5.5 mL) was added dropwise under N ₂ atmosphere. After 30' at room temperature, a solution of the two isomers (IVb) (2.5 g, 0.00566 mol) in.anhydrous DMF (10 mL) was added to the mixture, that was stirred at room temperature for 12 hrs (TLC monitoring: (cyclohexane/AcOEt 8:2). DMF was distilled under vacuum and the residue was diluted with water and extracted with CH ₂ Cl ₂ . The organic phase was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a mixture of two isomers of compound (Vc) (2.92 g), that was purified by flash chromatography on silica (cyclohexane/ AcOEt 8:2) to give the isomer (Vci) (0.97 g) and the isomer (Vc ₂ ) (0.35 g) as yellow oils. Yield: 42%.

(Vci) (isomer with lower elution time):

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.20 (s, 9H, Me ₃ Si), 0.86-0.93 (m, 5H, CH ₃ (CH ₂ ) ₃ + SiCH ₂ CH ₂ O), 1.29-1.38 (m, 2H, CH ₂ ), 1.54-1.61 (m, 2H, CH ₂ ), 1.76-1.80 (m, 2H, CH ₂ ), 1.97-2.00 (m, 6H, 3xCH ₂ ), 2.31 (t, J=7.8Hz, 2H, CH ₃ (CHz) ₂ CH ₂ ), 3.64 (t, J=8.2ηz, 2H, SiCH ₂ CH ₂ O), 4.68 (s, 2η, ArCH ₂ N), 5.77 (s, 2H, OCH ₂ N), 7.07-7.08 (m, 2H) 7.16-7.17 (m, 2H) 7.41-7.43 (m, IH) 7.46-7.56 (m, 2H) 7.85-7.87 (m, IH) (aromatic protons).

(Vc ₂ ) (isomer with higher elution time):

¹ H-NMR (400 MHz, CDCl ₃ , S): -0.09 (s, 9H, Me ₃ Si), 0.70 (t, J=8.4Hz, 2H, SiCH ₂ CH ₂ O), 0.86 (t, J=7.2Hz, 3H, CH ₃ ), 1.29-1.35 (m, 2H, CH ₂ ), 1.51-1.59 (m, 2H, CH ₂ ), 1.78-1.85 (m, 2H, CH ₂ ), 1.90-2.00 (m, 6H ₅ 3xCH ₂ ), 2.27 (t, J=7.8Hz, 2H, CH ₃ (CH ₂ ) ₂ CH ₂ ), 3.39 (t, J=8.4ηz, 2H, SiCH ₂ CH ₂ O), 4.64 (s, 2η, ArCH ₂ N), 5.04 (s, 2H, OCH ₂ N), 7.05-7.08 (m, 2H) 7.10-7.12 (m, 2H) 7.51-7.60 (m, 3H) 7.64-7.68 (m, IH) (aromatic protons).

Step II: 2-Butyl-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]-l, 3-diazaspiro[4.4]non- l-en-4-one (irbesartan) (Id)

a) Removal of the SEM group with HCVEtOH

To a solution of the compound (Vc) (0.12 g, 0.000219 mol) in EtOH (2.2 mL) was added HCl IN (2.2 mL). The solution was heated at 5O ⁰ C for 3 hrs (TLC monitoring: CH ₂ Cl ₂ MeOH 9:1) and then extracted with CHCl ₃ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Id) (0.090 g) Yield: 96%.

¹ H-NMR (400 MHz, CD ₃ OD, S): 0.86 (t, J=7.4Hz, 3H, CH ₃ ), 1.27-1.36 (m, 2H, CH ₂ ), 1.50 (t, J=7.6Hz, 2H, CH ₂ ), 1.79 (bs, CH ₂ ), 1.92-1.9^ (m, 6H, CH ₂ ), 2.38 (t, J=7.6Hz, 2H, CH ₂ ), 4.75 (s, 2H, NCH ₂ ), 7.10-7.15 (m, 4H) 7.52-7.56 (m, 2H) 7.63-7.64 (m, 2H) (aromatic protons) ppm.

b) Removal of the SEM group with HCl/THF

To a solution of the compound (Vc) (0.11 g, 0.0002014 mol) in THF (2 mL) was added HCl IN (2 mL). The solution was heated at 65 ⁰ C for 7 hrs (TLC monitoring: CH ₂ Cl ₂ MeOH 9:1) and then extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Id) (0.08 g)

Yield: 93%.

c) Removal of the SEM group with HCl/Acetone

To a solution of the compound (Vc) (0.14 g, 0.0002564 mol) in acetone (2.6 mL) was added HCl IN (2.6 mL). The solution was heated at 56°C for 9 hrs (TLC monitoring: CH ₂ Cl ₂ ZMeOH 9:1) and then extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Id) (0.1 g) Yield: 91%.

Example 6:

(5-MethyI-2-oxo-l,3-dioxol-4-yI)methyl 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2- (2H-tetrazoI-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxyla te (olmesartan medoxomil) (Ie)

Step I: 5-(2-Hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(N-(2-trimethylsi lylethoxymethyl) tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-ethylcarboxyl ate (Vd)

2-Propyl-5-[(l-hydroxy-l-methyl)ethyl]-3H-imidazole-4-ethylc arboxylate (0.808 g, 0.0033675 mol) was added to the two isomers (IVb) (1.5 g, 0.0033675 mol) and K ₂ CO ₃ (0.558 g, 0.0040382 mol) in anhydrous DMF (10 mL) under N ₂ atmosphere. The mixture was stirred at room temperature for 17 hrs (TLC monitoring: cyclohexane/AcOEt 6:4). The mixture was partitioned between water and AcOEt. The organic layer was washed with water (3 times), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue (1.8 g) that was purified by flash chromatography on silica (cyclohexane/AcOEt 6:4) to give the isomer (Vd ₁ ) (0.499 g) and the isomer (Vd ₂ ) (0.206 g) as oils. Yield: 35%.

(Vd ₁ ) (isomer with lower elution time):

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.03 (s, 9H, Me ₃ Si), 0.92 (t, J=8.2Hz, 2H, SiCH ₂ CH ₂ O), 0.96 (t, J=7.2Hz, 3H, CH ₂ CH ₂ CH ₃ ), 1.18 (t, J=7.2ηz, 3H, OCH ₂ CHi), 1.64 (s, 6η, CMe ₂ ), 1.67-1.76 (m, 2H ₅ CH ₂ CH ₂ CH ₃ ), 2.66 (t, J=7.6Hz, 2H, CH ₂ CH ₂ CH ₃ ), 3.66 (t, J=8.2Hz, 2H, SiCH ₂ CH ₂ O), 4.22 (q, J=7.2ηz, 2H, OCH ₂ CH ₃ ), 5.44 (s, 2H, ArCH ₂ N), 5.78 (s, 2H, OCH ₂ N), 6.84-6.86 (m, 2H) 7.14-7.16 (m, 2H) 7.41-7.43 (m, IH) 7.46-7.56 (m, 2H) 7.84- 7.86 (m, IH) (aromatic protons).

(Vd ₂ ) (isomer with higher elution time): ¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.10 (s, 9H, Me ₃ Si), 0.70 (t, J=8.4Hz, 2H, SiCH ₂ CH ₂ O), 0.92 (t, J=7.4Hz, 3H, CH ₂ CH ₂ CH ₅ ), 1.13 (t, J=7.0ηz, _. 3η, OCH ₂ CH ₃ ), 1.60 (s, 6η, CMe ₂ ), 1.62-1.71 (m, 2H, CH ₂ CH ₂ CH ₃ ), 2.58 (t, J=7.8Hz, 2H, CH ₂ CH ₂ CH ₃ ), 3.39 (t, J=8.4Hz, 2H, SiCH ₂ CH ₂ O), 4.17 (q, J=7.2ηz, 2H, OCH ₂ CH ₃ ), 5.05 (s, 2H, ArCH ₂ N), 5.38 (s, 2H, OCH ₂ N), 6.81-6.83 (m, 2H) 7.05-7.07 (m, 2H) 7.49-7.52 (m, 2H) 7.55-7.57 (m, IH) 7.61- 7.65 (m, IH) (aromatic protons).

Step II: 5-(2-Hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(N-(2-trimethylsi lylethoxymethyl) tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid (Ve i)

A solution of NaOH (0.052 g, 0.001311 mol> in water (1 mL) was added to compound (VdO (0.262 g, 0.0004337 mol) in THF (1 mL). The mixture was stirred at room temperature for 23 hrs (TLC monitoring: CH ₂ Cl ₂ /MeOH/AcOH 85:10:5). HCl IN was added until pH 4 was reached. The mixture was extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Vei) (0.261 g) as a white solid, m.p. 68-69°C. Yield: 99%.

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.05 (s, 9H, Me ₃ Si), 0.86 (t, J-7.2Hz, 3H, CH ₂ CH ₂ CH ₃ ), 0.89 (t, J=8.1ηz, 2H, SiCH ₂ CH ₂ O), 1.54-1.60 (m, 2H, CH ₂ CH ₂ CH ₃ ) 1.67 (s, 6H, CMe ₂ ), 2.94 (t, J-7.2Hz, 2H, CH ₂ CH ₂ CH ₃ ), 3.65 (t, J=8.1Hz, 2H, SiCH ₂ CH ₂ O), 5.75 (s, 2η, ArCH ₂ N), 5.79 (s, 2H, OCH ₂ N), 6.97-6.99 (m, 2H) 7.12-7.14 (m, 2H) 7.35-7.38 (m, IH) 7.44-7.53 (m, 2H) 7.83-7.85 (m, IH) (aromatic protons).

Step III: 4-Bromomethyl-5-methyl~l,3-dioxol~2-one

A mixture of 4,5-dimethyl-l,3-dioxol-2-one (1.5 g, 0.013158 mol), NBS (2.34 g, 0.013158 mol) and benzoyl peroxide (0.089 g, 0.0003684 mol) in CCl ₄ (20 mL) was stirred at 77°C for 6 hrs (TLC monitoring: cyclohexane/AcOEt 6:4). The solution was treated with an aqueous solution OfNaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 4-bromomethyl-5 -methyl- 1,3- dioxol-2-one (2.34 g). Yield: 92%.

¹ H-NMR (400 MHz, CDCl ₃ , δ): 2.13 (s, 3H, CH ₃ ), 4.18 (s, 2H, CH ₂ Br).

Stέp IV: (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 5-(2~hydroxypropan-2-yl)-2-propyl-3-[[4- [2-(N-(2-trimethylsilylethoxymethyl)tetrazol-5-yl)pherψl]ph enyl]methyl]imidazole-4- carboxylate (Vf ₁ )

A mixture of the compound (Ve ₁ ) (0.260 g, 0.0004516 mol), 4-bromomethyl-5-methyl-l,3- dioxol-2-one (0.1 g, 0.000518 mol) and K ₂ CO ₃ (0.033 g, 0.000239 mol) in anhydrous DMF (1.5 mL) was stirred for 1.5 hrs at room temperature under N ₂ atmosphere (TLC monitoring: CH ₂ Cl ₂ /Me0H/Ac0H 85:10:5). The mixture was partitioned between a saturated solution of NaHCO ₃ and AcOEt. The organic phase was washed with water (3

times), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Vf ₁ ) (0.3042g) as a yellow oil. Yield: 98%.

¹ H-NMR (400 MHz, CDCl ₃ , δ): -0.02 (s, 9H, Me ₃ Si), 0.92 (t, J=8.1Hz, 2H, SiCH ₂ CH ₂ O), 0.98 (t, J=7.2Hz, 3H, CH ₂ CH ₂ CH ₃ ), 1.64 (s, 6η, CMe ₂ ), 1.70-1.80 (m, 2H, CH ₂ CH ₂ CH ₃ ), 2.07 (s, 3H, CH ₃ C=C), 2.76 (m, 2H, CH ₂ CH ₂ CH ₃ ), 3.67 (t, J=8.1Hz, 2H, SiCH ₂ CH ₂ O), 4.89 (s, 2η, COOCH ₂ ), 5.41 (s, 2H, ArCH ₂ N), 5.79 (s, 2H, OCH ₂ N), 6.80-6.82 (m, 2H) 7.14-7.16 (m, 2H) 7.44-7.52 (m, 2H) 7.54-7.58 (m, IH) 7.85-7.87 (m, IH) (aromatic protons).

Step V: (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 5-(2-hydroxypropan-2-yl)~2~propyl~3-[[4- [2~(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carbox ylate (olmesartan medoxomil) (Ie)

NaHSO ₄ -SiO ₂ (0.24 g) was added to the compound (Vf ₁ ) (0.086 g, 0.000125 mol) in CH ₂ Cl ₂ /MeOH 9:1 (2 mL). The mixture was heated at 50°C for 10 hrs. The organic phase was concentrated under reduced pressure. The solid residue was washed with warm AcOEt and filtered. The organic phase was concentrated under reduced pressure to give the compound (Ie) (0.0512 g). Yield: 73%.

¹ H-NMR (400 MHz, CD ₃ OD, δ): 0.93 (t, J=7.4Hz, 3H, CH ₂ CH ₂ CH ₅ ), 1.58 (s, 6η, (CH ₃ ) ₂ C), 1.58-1.66 (m, 2H, CH ₂ CH ₂ CH ₃ ), 2.06 (s, 3H, CH ₃ C=C), 2.71 (t, J=7.6ηz, 2H, CH ₂ CH ₂ CH ₃ ), 5.01 (s, 2H, NCH ₂ ), 5.50 (s, 2H, OCH ₂ ), 6.86 (d, J=8.2Hz, 2H) 7.07 (d, J=8.2Hz, 2H) 7.52-7.58 (m, 2H) 7.62-7.67 (m, 2H) (aromatic protons).

Example 7:

2-Ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl] benzimidazoIe-4-carboxyIic acid (candesartan) (If)

Step I: 2-Amino-3-nitro-benzoic acid ethyl ester (VII)

HCl IN (10 niL) [a solution of HCl IN (25 mL) was prepared by dropwise acetyl chloride (1.78 mL) in MeOH (3.22 mL) and diluting with AcOEt (20 mL)] was slowly added dropwise to ethyl 2-[(fert-butoxycarbonyl)amino]-3-n _. itrobenzoate (VI) (1 g, 0.00323 mol), under N ₂ atmosphere, at 0 ⁰ C. The solution was kept at 0°C for 5', than stirred at room temperature for 64 hrs (TLC monitoring: cyclohexane/AcOEt 2:1). A saturated solution of NaHCO ₃ was added to the mixture and the mixture was extracted several times with AcOEt. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (VII) (0.67 g) as a yellow solid, m.p. 108°C. Yield: 99%.

[ ¹ H] NMR (400 MHz, CDCl ₃ , δ): 1.40 (t, J=7.1Hz, 3H, OCH ₂ CH ₅ ), 4.37 (q, J=7.1ηz, 2H, OCH ₂ CH ₃ ), 6.65 (dd, J=8.0Hz, 8.0Hz, IH) 8.25 (dd, J=7.6Hz, 1.2Hz, IH) 8.37 (dd, J=7.6Hz, 1.2Hz, IH) (aromatic protons), 8.46 (bs, 2H, NH ₂ ).

Step II: 2,3-Diamino-benzoic acid ethyl ester (VIII)

To a solution of compound (VII) (0.67 g, 0.00319 mol) in AcOEt (30 mL) was added Pd/C (10%) (0.05 g) and the mixture subjected to hydrogenation at 50 psi at room temperature for 30 hrs (TLC monitoring: cyclohexane/AcOEt 2:1). The mixture was filtered and concentrated under reduced pressure to give the compound (VIII) (0.57 g) as a light brown solid, m.p. 56-57°C. Yield: 99%.

[ ¹ H] NMR (400 MHz, CDCl ₃ , δ): 1.38 (t, J=7.1Hz, 3H, OCH ₂ CTf ₅ ), 4.30 (bs, 4H, NH ₂ ), 4.33 (q, J=7.1Hz, 2H, OCH ₂ CH ₃ ), 6.60 (dd, J=8.2Hz, 7.6Hz, IH) 6.84 (d, J=7.6Hz, IH) 7.49 (d, J=8.2Hz, IH) (aromatic protons).

Step III: 2-Ethoxy-3H-benzimidazole-4-ethylcarboxylate (IX)

Tetraethylorthocarbonate (0.72 g, 0.0037449 mol) was slowly added dropwise to a solution of compound (VIII) (0.55 g, 0.0030555 mol). in AcOH (2 mL), under N ₂ atmosphere, at 0°C. The solution was kept at O ⁰ C for 5', than stirred at room temperature for 3 hrs (TLC monitoring: cyclohexane/AcOEt 2:1). Water (5 mL) was added to the mixture, at 0°C. The mixture was stirred at 0 ⁰ C for 1 hr. The precipitated solid was filtered, washed with water and dried under vacuum, to give the compound (IX) (0.58 g) as a white solid, m.p. 98- 99°C. Further 0.12 g of the compound (IX) were recovered from wash and filtering water. Yield: 87%.

[ ¹ H] NMR (400 MHz, CDCl ₃ , δ): 1.44 (t, J=7.1Hz, 3H, OCH ₂ CH ₃ ), 1.50 (t, J=7.1ηz, 3H, OCH ₂ CH ₃ ), 4.44 (q, J=7.1ηz, 2H, OCH ₂ CH ₃ ), 4.67 (q, J=7.1Hz, 2H, OCH ₂ CH ₃ ), 7.21 (dd, J=8.0Hz, 7.6Hz, IH) 7.74 (d, J=7.6Hz, IH) 8.0 (d, J=8.0Hz, IH) (aromatic protons), 9.55 (bs, IH ₅ NH).

Step IV: 2-Ethoxy-3-{2 '-[l-(2-trimethylsilylethoxymethyl)-lH-tetrazol-5-yl]-biphen yl-4- ylrnethyl}-3H-benzimidazole-4-ethylcarboxylat& (Vg)

The two isomers (IVb) (0.1467 g, 0.0003293 mol), K ₂ CO ₃ (0.065 g, 0.0004706 mol) and compound (IX) (0.1 g, 0.0004314 mol) were dissolved in anhydrous DMF (2 mL) at room temperature, under N ₂ atmosphere. The mixture was stirred at room temperature for 20 hrs (TLC monitoring: cyclohexane/AcOEt 8:2). Ice and a saturated solution of NaCl were added to the mixture, at 0 ⁰ C. The mixture was extracted with CH ₂ Cl ₂ .The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 0.2312 g of a

mixture that was purified by flash chromatography on silica (cyclohexane/ AcOEt 8:2) to give the isomer (VgO (0.066 g) and the isomer\(Vg ₂ ) (0.037 g) as oils. Yield: 52%.

(Vg ₁ ) (isomer with lower elution time)

[ ¹ H] NMR (400 MHz, CDCl ₃ , δ): -0.04 (s, 9H, Si(CH ₃ ) ₃ ), 0.866 (t, J=8.2Hz, 3H, SiCH ₂ CH ₂ O), 1.24 (t, J=7.2Hz, 3H, OCH ₂ CH ₃ ), 1.48 (t, J=7.2ηz, 3H, OCH ₂ CH ₃ ), 3.57 (t, J=8.2ηz, 3H, SiCH ₂ CH ₂ O), 4.21 (q, J=7.2ηz, 2H, OCH ₂ CH ₃ ), 4.66 (q, J=7.2Hz, 2H, OCH ₂ CH ₃ ), 5.62 (s, 2H, PhCH ₂ N), 5.70 (s, 2H, OCH ₂ N), 6.88 (d, J=8.4Hz, 2H) 7.04 (d, J=8.0Hz, 2H) 7.16 (dd, J=8.0Hz, 7.6Hz, IH) 7.36 (dd, J=7.6Hz, 1.2Hz, IH) 7.42-7.53 (m, 3H) 7.71 (d, J=8.0Hz, IH) 7.82 (dd, J=7.6Hz, 1.2Hz, IH) (aromatic protons).

(Vg ₂ ) (isomer with higher elution time)

[ ¹ H] NMR (400 MHz, CDCl ₃ , δ): -0.13 (s, 9H ₅ Si(CH ₃ ) ₃ ), 0.64 (t, J=8.4Hz, 3H, SiCH ₂ CH ₂ O), 1.27 (t, J=7.2Hz, 3H, OCH ₂ CH ₃ ), 1.46 (t, J=7.0ηz, 3H, OCH ₂ CH ₃ ), 3.31 (t, J=8.4ηz, 3H, SiCH ₂ CH ₂ O), 4.20 (q, J=7.2ηz, 2H, OCH ₂ CH ₃ ), 4.64 (q, J=7.0Hz, 2H, OCH ₂ CH ₃ ), 4.89 (s, 2H, PhCH ₂ N), 5.57 (s, 2H, OCH ₂ N), 6.88 (d, J=8.0Hz, 2H) 6.97 (d, J=8.0Hz, 2H) 7.15 (dd, J=8.0Hz, 8.0Hz, IH) 7.49 (d, J=8.8Hz, IH) 7.54-7.61 (m, 3H) 7.69- 7.74 (m, 2H) (aromatic protons).

Step V: 2-Ethoxy-3-{2 '-[l-(2-trimethyl$tiylethoxymethyl)-lH-tetrazol-5-yl]-biphen yl-4- ylmethyl}-3H-benzimidazole-4-carboxylic acid (Vh)

A solution of NaOH (0.033 g, 0.0008152 mol) in water (2 mL) was added to compound (Vgi) (0.1552 g, 0.0002591 mol) in MeOH (2 mL). The solution was heated at 70°C for 17 hrs (TLC monitoring: cyclohexane/AcOEt 2:1). HCl 2N (5 mL) was added. The mixture was extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the compound (Vhj) (0.13 g) as a white solid, m.p. 62-64°C.

Yield: 88%.

[ ¹ H] NMR (400 MHz, CDCl ₃ , <5): -0.03 (s, 9H, Si(CHa) ₃ ), 0.92 (t, J=8.4Hz, 3H, SiCH ₂ CH ₂ O), 1.48 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 3.63 (t, J=8.4ηz, 3H, SiCH ₂ CH ₂ O), 4.69 (q, J=7.0ηz, 2H, OCH ₂ CH ₃ ), 5.68 (s, 2H, PhCH ₂ N), 5.75 (s, 2H, OCH ₂ N), 6.87 (d, J=8.0Hz, 2H) 7.01 (d, J=8.0Hz, 2H) 7.17 (dd, J=7.6Hz, 8.0Hz, IH) 7.36 (dd, J=7.4Hz, 1.4Hz, IH) 7.43-7.50 (m, 2H) 7.64 (d, J=7.6Hz, IH) 7.78 (d, J=7.6Hz, IH) 7.87 (dd, J=7.4Hz, 1.4Hz, IH) (aromatic protons).

Step VI: 2-Ethoxy~3-[[4-[2-(2H-tetrazol~5-yl)phenyl]phenyl]methyl]ben zimidazole-4' carboxylic acid (candesartan) (If)

TBAF (1 M in THF) (0,17 mL, 0,17 mmol) was added to compound (Vh ₁ ) (48,8 mg, 0.085 mmol) under N ₂ atmosphere. The solution was heated at 6O ⁰ C for 36 hrs (TLC monitoring: CHCl ₃ /CH ₃ OH/AcOH 8:2:0.2). The solvent was evaporated under reduced pressure. The residue was taken up in an aqueous saturated solution of Na ₂ CO ₃ - and washed three times with CH ₂ Cl ₂ . Glacial AcOH was added to the aqueous phase until pH 5-6 was reached. The acid aqueous phase was extracted with CH ₂ Cl ₂ , that was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give compound (If) as a white solid, m.p. 183-185 Yield: 70%.

[ ¹ Hl NMR (400 MHz, CDCl ₃ , S): 1.39 (t, J=7.2Hz, 3H, OCH ₂ CHj), 4.55 (q, J=7.2ηz, 2H, OCH ₂ CH ₃ ), 5,39 (bs, 2H, CH ₂ N), 6.62 (d, 2η, J=7.2Hz, aromatic protons), 6.74 (d, 2H, J=7.2Hz, aromatic protons), 7.05 (t, IH, J=8Hz, aromatic protons), 7.28-7.46 (m, 4H) 7.56 (d, IH, J=7.2Hz, aromatic protons), 7.63 (d, IH, J=8Hz, aromatic protons).

Example 8:

Preparation of the NaHSO _j -SiO? reagent system

SiO ₂ (60 A, 200-400 mesh, 5 g) was added to a solution OfNaHSO ₄ (1.8 g, 0.015 mol) in water (10 mL). The mixture was stirred for about 15 minutes and weakly heated over a plate until a white fine powder was obtained. The supported reactant was dried in a heater at 120°C for at least 48 h, before its use.