MXPA06008678A - Coupling reactions useful in the preparation of (1h-tetrazol-5-yl)-biphenyl derivatives - Google Patents

Abstract

The present invention relates to a process for the manufacture of intermediates that may be used for the manufacture of ARBs (also called angiotension II receptor antagonists or AT1 receptor antagonists) comprising as a common structural feature a (lH-tetrazol-5-yl)-biphenyl ring. Form PCT/ISA/210 (continuation of first sheet (3)) (January 2004)

Description

USEFUL COUPLING REACTIONS IN THE PREPARATION OF DERIVATIVES OF (1 H-TETRAZOL-5-ID-BIFENILO The present invention relates to a process for the manufacture of intermediates that can be used for the manufacture of ARBs (also referred to as angiotensin II receptor antagonists or AT ^ receptor antagonists, which comprise a tetrazole ring as a structural feature For example, angiotensin II receptor antagonists can be used for the treatment of hypertension and related diseases and conditions.

For example, mention may be made of angiotensin II receptor antagonists that are selected from the group consisting of valsartan (see European Patent Number EP 443983), losartan (see European Patent Number EP 253310), candesartan (see the European Patent Number EP 459136), eprosartan (see European Patent Number EP 403159), rbesartan (see European Patent Number EP 45451 1), olmesartan (see European Patent Number EP 503785), and tasosartan (see European Patent Number EP 539086), or in each case, a pharmaceutically acceptable salt thereof.

More specifically, all of these angiotensin receptor antagonists I I comprise the following common structural element of the Formula (A): The manufacture of an aldehyde of Formula (I A), which corresponds to the element of Formula (A), is a critical step in the manufacture of the above-mentioned angiotensin II receptor antagonists. Various aryl-aryl coupling reactions have been recommended in the art to form the biphenyl moiety in an aldehyde of the Formula (I A). European Patent Number EP 550313 describes the preparation of protected 2 '- (1 H-tetrazol-5-yl) -biphenyl-4-carbaldehyde, which involves the transition metal catalyzed coupling of 5- (2-iodophenyl) -2H -tetrazole protected with an organozinc reagent or an aryl boronic acid. the formation of stoichiometric quantities of the zinc salt waste in the first case, and the different chemical steps required for the preparation of the aryl boronic acid in the second case, and the formation of stoichiometric amounts of the iodide waste in both cases, considered as disadvantages. U.S. Patent No. US 5468867 discloses the preparation of protected 2 '- (1 H-tetrazol-5-yl) -biphenyl-4-carbaldehyde, which involves the metalation of an aryl halide with a organometallic base, such as an alkyl lithium reagent, followed by coupling, for example, with protected 5- (2-methoxy-phenyl) -2H-tetrazole. A drawback of this process is the formation of stoichiometric amounts of waste containing reactive halogen. The aim of the present invention is to provide a novel synthesis for the compounds of Formulas (I) and (I C): wherein Y is a tetrazole protecting group, R-, and R2, independently of one another, represent alkyl of 1 to 10 carbon atoms, or R- and R2 combined together form alkylene of 2 to 10 carbon atoms, and R3 represents a hydroxyl protecting group, which (1) does not have the drawbacks described above, (2) it allows to make use of these tetrazole protecting groups, which are easily removed in the presence of a Bronsted acid, (3) no it requires large excesses of reagents, (4) it gives high yields, (5) it gives a minimum of waste, in particular there are no stoichiometric quantities of reactive or problematic waste for the environment, and (6) it is economically attractive. The compounds of Formulas (I) and (IC) can be readily converted to compounds of Formula (IA), and therefore, are important intermediates for the manufacture of angiotensin II receptor antagonists having a structural characteristic corresponding to Formula (A), as described, for example, in the International Application of TCP Number WO 04/026847. Surprisingly, it has been found that the process according to the present invention satisfies at least the above objectives. In one aspect, the present invention relates to a process for the manufacture of a compound of Formula (I): wherein Y represents a tetrazole protecting group, and R, and R2, independently of one another, represent alkyl of 1 to 10 carbon atoms, or R-, and R2 combined together form alkylene of 2 to 10 carbon atoms; which comprises: (a) reacting a compound of the Formula (I I a): wherein Hal is chlorine, bromine, or iodine, with an active form of magnesium in an appropriate solvent; (b) reacting an aryl magnesium halide compound resulting from Formula (II b): in the presence of a transition metal catalyst and an effective catalytic amount of a metal salt additive, with a compound of the Formula (II c): wherein X is a substituent which, when linked to a phenyl ring, is not substantially replaceable at room temperature by an aryl magnesium halide reagent of the Formula (I I b) in the absence of a catalyst; and if necessary, isolating a compound resulting from Formula (I).

In another aspect, the present invention relates to a process for the manufacture of a compound of the Formula (I C): wherein Y represents a tetrazole protecting group, and R3 represents a hydroxyl protecting group, which comprises: (a ') reacting a compound of the formula (11): a), wherein Hal is chlorine, bromine, or iodine, with an active form of magnesium in an appropriate solvent; (b ') reacting an aryl magnesium halide compound resulting from the Formula (11): in the presence of a transition metal catalyst and a catalytically effective amount of a metal salt additive, and with a compound of the Formula (I I c): wherein X is a substituent, which, when linked to a phenyl ring, is not substantially replaceable at room temperature by an aryl magnesium halide reagent of the Formula (11 l b) in the absence of a catalyst; and if necessary, isolating a compound resulting from Formula (I C). A further aspect of the present invention is to combine steps (a) and / or (b), or steps (a ') and / or (b'), with a subsequent deprotection step (c), resulting in the formation of a compound of Formula (IA) or (IB): respectively. The resulting compound of Formula (I A) or (1 B), respectively, is subsequently isolated, and can be employed as an intermediate in the preparation of angiotensin receptor antagonists I I, as referred to hereinbefore. It is obvious to those skilled in the art that a compound of Formula (I B) can be readily converted to a compound of Formula (I A) by its treatment with an oxidizing agent according to methods well known in the art. The reactions described above and below in the variants are carried out, for example, in the absence or, by custom, in the presence of a suitable solvent or diluent, or a mixture thereof, the reaction being carried out, according to is required, with cooling, at room temperature, or with heating, for example in a temperature range from about -80 ° C to the boiling point of the reaction medium, preferably from about -10 ° C to about 140 ° C , and if necessary, in a closed vessel, under pressure, in an inert gas atmosphere, and / or under anhydrous conditions.

The purpose of introducing protecting groups, for example Y and R3, is to protect the functional groups, for example the tetrazole group and a hydroxyl group, respectively, from the undesired reactions with the reaction components under the conditions used to carry out the process of the present invention. The choice of protecting groups is known to those skilled in the art, and depends on the nature of the functional group to be protected, or on the reaction conditions. Well-known protecting groups that satisfy these conditions, and their introduction and removal, are described, for example, in McOmie, "Protective Groups in Organic Chemistry," Plenum Press London, NY (1973); and in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, I nc. , NY (1999). A tetrazole protecting group (Y) is selected, for example, from the group consisting of tertiary alkyl of 4 to 7 carbon atoms, such as tertiary butyl; methyl which is substituted by 1, 2, or 3 substituents selected from alkyl of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms, for example 1-ethoxy-ethyl, 1-methoxy-1-methyl- ethyl; 2-tetrahydropyranyl; 2-tetrahydrofuranyl; alkyl of 1 to 2 carbon atoms which is mono-, di-, or tri-substituted by phenyl, such as benzyl or benzhydryl, or trityl, wherein the phenyl ring is unsubstituted or substituted by one or more, for example 2 or 3 substituents, for example those selected from the group consisting of tertiary alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms; piperonyl; 1-methyl-1-phenyl-ethyl; fluorenyl; methyl-thiomethyl; silyl, such as tri-alkyl of 1 to 4 carbon atoms-silyl, for example trimethylsilyl, triethyl-lysyl, or tert-butyl-dimethylsilyl, or di-alkyl of 1 to 4 carbon atoms-phenyl- silyl, for example dimethylphenylsilyl; alkyl of 1 to 7 carbon atoms-sulfonyl; arylsulfonyl, such as phenylsulfonyl, wherein the phenyl ring is unsubstituted or substituted by one or more, for example two or three substituents, for example those selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms; alkanoyl of 2 to 8 carbon atoms, such as acetyl or valeroyl; and esterified carboxyl, such as alkoxy of 1 to 7 carbon atoms-carbonyl, for example methoxy-, ethoxy-, or tert-butyloxy-carbonyl. In the same way, a protecting group of tetrazole (Y) can also be a cation, for example of an alkali metal or an alkaline earth metal, for example Li (l), Na (i), K (l), Rb (l), Cs (l), Mg (ll), Ca (ll), and Sr (ll). Examples of preferred protecting groups (Y) are terbutyl, benzyl, p-methoxy-benzyl, 3,4-dimethoxy-benzyl, 1-methyl-1-phenyl-ethyl, triphenyl-methyl, (p-methoxy-phenyl) -diphenyl-methyl, benzyloxy-methyl, methoxymethyl, ethoxy-methyl, 1-butoxy-ethyl, 1-ethoxy-ethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-methoxy-1-methyl-ethyl, 1-methoxy- cyclohexyl, 1-ethoxy-cyclohexyl, trimethyl-silyl, and triethylsilyl. Particularly preferred protecting groups (Y) are 1-butoxy-ethyl, 1-ethoxy-ethyl, 2-tetrahydropyranyl, and 2-tetrahydrofuranyl. A hydroxyl protecting group (R3) is selected, for example, from the group consisting of tertiary alkyl of 4 to 7 carbon atoms, such as tertiary butyl; methyl that is replaced by 1, 2, or 3 substituents selected from alkyl of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms, for example 1-ethoxy-ethyl, 1 - . 1-methoxy-1-methyl-ethyl; 2-tetrahydropyranyl; 2-tetrahydrofuranyl; alkyl of 1 to 2 carbon atoms which is mono-, di-, or tri-substituted by phenyl, such as benzyl or benzhydryl or trityl, wherein the phenyl ring is unsubstituted or substituted by one or more, for example 2 or 3 substituents, for example those selected from the group consisting of tertiary alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms; piperonyl; 1-methyl-1-phenyl-ethyl; fluorenyl; methyl-thiomethyl; silyl, such as tri-alkyl of 1 to 4 carbon atoms-silyl, for example trimethylsilyl, triethylsilyl, or tert-butyl-imethyl-siyl, or di-alkyl of 1 to 4 carbon atoms-phenyl- silyl, for example dimethylphenylsilyl; 2,2-dimethyl-propanoyl (ie, pivaloyl), and esterified carboxyl, such as terbutyloxycarbonyl and benzyloxycarbonyl. Examples of the preferred R3 protecting groups are 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-butoxy-ethyl, and 1-ethoxy-ethyl. The general terms used hereinbefore and hereinafter, have the following meaning, unless otherwise defined: alkyl of 1 to 10 carbon atoms is, for example, alkyl of 1 to 7 carbon atoms , such as methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, tertiary butyl, or a corresponding residue of pentyl, hexyl, or heptyl. Alkyl of 1 to 4 carbon atoms, especially methyl or ethyl, is preferred.

Alkylene of 2 to 10 carbon atoms is, for example, alkylene of 2 to 6 carbon atoms, such as ethylene, propylene, butylene, 1,2-dimethyl-ethylene, 2,2-dimethyl-propylene, or 1,4. dimethyl-1, 4-butylene. Preference is given to alkylene of 2 to 4 carbon atoms, especially ethylene or propylene. Hal represents in particular chlorine and bromine. Alkoxy of 1 to 7 carbon atoms is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, or a corresponding residue of pentyloxy, hexyloxy, or heptyloxy. Alkoxy of 1 to 4 carbon atoms is preferred. Methoxy, ethoxy, and butoxy are especially preferred. Alkanoyl of 2 to 8 carbon atoms is, for example, alkanoyl of 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl, valeroyl, or pivaloyl. Acetyl is especially preferred.

Steps (a) and (a '): An active form of magnesium is, for example, magnesium burrs of the type normally used for these transformations, magnesium bits, magnesium powder, or magnesium sticks. Additionally, an active form of magnesium is magnesium which is activated by a catalytic amount of iodine, bromine, 1,2-dibromo-ethane, a hydride reagent, or the aryl magnesium halide reagent intended to be prepared. An adequate amount of magnesium is from 1.0 to 1.08 molar equivalents, preferably from 1.0 to 1.2 molar equivalents, with respect to the amount of a compound of the Formula (I I a) or (II l a) used. The reaction is carried out, for example, in a suitable inert solvent or in a mixture of solvents. Conventionally inert solvents do not react with the corresponding starting material of Formula (I I a) or (ll a). Suitable solvents are the etheral solvents, such as ethyl ether, tert-butyl methyl ether, tetrahydrofuran, butyl ether, 1,2-dimethoxyethane, or 1,2-diethoxy ethane, or a mixture of two or more of these solvents, or a mixture of one of these solvents and an aromatic solvent, such as toluene or xylene. A preferred solvent is tetrahydrofuran. A suitable reaction temperature is preferably between 0 ° C and 75 ° C, more preferably between 10 ° C and 35 ° C.

Steps (b) v ib '): A coupling step (b) or (b') is carried out in the presence of a transition metal catalyst. A suitable transition metal is, for example, nickel, palladium, platinum, cobalt, manganese, or copper. A useful transition metal salt is, for example, a salt of nickel (ll), of palladium (ll), of platinum (ll), of cobalt (ll), of manganese (ll), of copper (l), or copper (ll), such as chloride, bromide, iodide, hydroxide, oxide, acetate, hydroxy-acetate, propionate, succinate, trifluoro-acetate, acetylacetonate, nitrate, cyanide, sulfate, trifluoro-methane-sulfonate, methanesulfonate, benzene -sulfonate, or p-toluene sulfonate thereof. A suitable transition metal catalyst is preferably a complex of a transition metal or a transition metal salt, and one, two, or up to four coordination ligands. The transition metal catalyst can be preformed, or it can be generated in situ in the reaction mixture. A suitable transition metal catalyst can also be an uncomplexed transition metal in its elemental form, or an uncomplexed transition metal salt. The uncomplexed transition metal or its salt can be supported on carbon, silica, alumina, or diatomaceous earth. Suitable ligands are olefins, such as 1,5-cyclo-octadiene; tri- (C 1-4 -alkyl) -amines, such as triethylamine and ethyl-di-isopropylamine; N-alkyl of 1 to 4 carbon atoms-piperidines, such as N-piperidine; N, N, N ', N'-tetramethylethylene diamine; heterocyclic amines and diamines, such as pyridine, N-methyl-imidazole, 2,2'-d-pyridyl, 1, 10-phenanthroline, wherein the ring is unsubstituted or substituted by one or more, for example two or three alkyl residues of 1 to 4 carbon atoms, as for example in collidine; linear and cyclic ethers containing two or more, for example 3 or 4 oxygen atoms, such as 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, di- (ethylene glycol) -dimethyl ether, and 1, 2-dimethoxy-benzene. Particularly suitable ligands are those which contain one or two trivalent phosphorus atoms, for example triphenylphosphine, tri- (orfo-tolyl) -phosphine, and tri- (para-tolyl) -phosphine; tri- (C 1-8 alkyl) -phosphines, such as trimethyl-phosphine, triethyl-phosphine, tributyl-phosphine, tri- (1,1-dimethyl-ethyl) -phosphine; tri- (cycloalkyl of 4 to 7 carbon atoms) -phosphines, such as tricyclopentyl phosphine and tricyclohexyl phosphine; tri- (C 1-6 -alkyl) -phosphites, such as trimethyl-phosphite, triethyl-phosphite, and tri- (1-methyl-ethyl) -phosphite; tri- (cycloalkyl of 4 to 7 carbon atoms) -phosphites, such as tricyclopentylphosphite and tricyclohexylphosphite; 1, 2-bis- (diphenylphosphino) -ethane (ie, dppe), 1,3-bis- (diphenyl-phosphino) -propane (ie, dppp), 1,4-bis- (diphenyl-phosphino) ) -butane (ie, dppb), 1, 1 '-bis- (diphenyl-phosphino) -ferrocene (ie, dppf), 1,1'-bis- (di- [2-propyl] -phosphine) - Ferrocene, 1,1 '-bis- (di-tert-butyl-phosphino) -ferrocene, 1,2-bis- (diphenyl-phosphino) -benzene, 2,2'-bis- (diphenyl-phosphino) -1, -biphenyl (ie, BIPHEP), 2,2'-bis- (diphenyl-phosphino) -1, 1'-b-naphthyl (ie, BINAP), bis- (2-diphenyl-phosphino-phenyl) -ether (ie, DPEphos), 9,9-dimethyl-4,5-bis- (diphenyl-phosphino) -xanthene (i.e., XANTPHOS). The transition metal salts are derived from the above specific transition metals. Preferred transition metal salts are nickel chloride (11), nickel bromide (11), and nickel acetyl acetonate (11). A particularly preferred transition metal salt is nickel chloride (11). Preferred ligands are triphenyl-phosphine, 1,2-bis- (diphenyl-phosphino) -ethane (ie, dppe), 1,3-bis- (diphenyl-phosphino) -propane (ie, dppp), 1, 1 '-bis- (diphenyl-phosphino) -ferrocene (ie, dppf). A particularly preferred ligand is 1,2-bis- (diphenylphosphino) -ethane (ie, dppe). The preferred catalysts are dichloro-bis- (triphenyl-phosphino) -nickel (ll), dichloro- [1,2- bis- (diphenyl-phosphino) -ethane] -nickel (ll), dichloro- [1, 3] - bis- (diphenylphosphino) -propane] -nickel (ll). A particularly preferred catalyst is dichloro- [1,2-bis] - (diphenyl-phosphino) -ethane] -nickel (11).

The amount of nickel catalyst used is preferably between 0.05 and 2 mole percent relative to the N-protected tetrazole starting material of the Formula (IIC), preferably between 0.2 and 1.5 mole percent . In the same way, the preferred transition metal salts are palladium chloride (1), palladium bromide (1), and palladium acetate (1). A particularly preferred transition metal salt is palladium chloride (11). Preferred ligands are triphenyl-phosphine, 1,3-bis-diphenyl-phosphino) -propane (ie, dppp), 1,1 '-bis- (diphenyl-phosphino) -ferrocene (ie, dppf). A particularly preferred ligand is 1,1 '-bis- (diphenyl-phosphino) -ferrocene (ie, dppf). Preferred palladium catalysts are dichloro-bis- (triphenyl-phosphine) -palladium (II), dichloro- [1,3-bis- (diphenyl-phosphino) -propane] -palladium (II), and dichloro- [1, 1'-bis- (diphenyl-phosphino) -ferrocene] -palladium (II) or its dichloromethane adduct. A particularly preferred palladium catalyst is dichloro- [1,1'-bis- (diphenyl-phosphino) -ferrocene] -palladium (11), or a dichloromethane adduct thereof. The amount of palladium catalyst used is preferably between 0.01 and 1 mole percent relative to the N-protected tetrazole starting material (11), preferably between 0.05 and 0.3 mole percent. The coupling reaction in step (b) or (b ') may involve a metal salt additive. The role of the metal salt additive, which is used in catalytic amounts, is to facilitate the coupling reaction. Compared to couplings with aryl zinc reagents, the use of catalytic amounts of this metal salt additive results in the formation of less waste. In addition, in the presence of the metal salt additive, higher conversions of the starting material (I I c) can be achieved. A useful metal salt additive is a copper (l), copper (ll), zinc (ll), silver (l), cadmium (ll), mercury (ll), aluminum ( III), gallium (11), indium (III), tin (IV), titanium (IV), and zirconium (IV). Examples of these salts are the corresponding chloride, bromide, iodide, carbonate, hydroxide, oxide, alkanoates of 1 to 7 carbon atoms such as acetate and propionate, alkoxides of 1 to 7 carbon atoms such as methoxide and ethoxide, trifluoro-acetate, acetyl-acetonate, nitrate, cyanide, sulfate, trifluoromethansulfonate, methanesulfonate, benzenesulfonate, or para-toluenesulfonate. Preferred metal salt additives are the zinc (1) salts, such as zinc chloride (11) and zinc bromide (11). A particularly preferred metal salt additive is zinc chloride (11). The amount of metal salt additive used is preferably between 0.1 and 8 mole percent relative to the N-protected tetrazole starting material of Formula (II c), preferably between 0.5 and 6 molar percent. The substituent X is a substituent which is not substantially replaceable at room temperature by an aryl magnesium halide reagent of the Formula (I I b) or (I ll b) in the absence of a transition metal catalyst. In particular, X is, for example, chlorine or bromine. A preferred substrate is chlorine. When X is chlorine, the preferred ionization rate of the cayalizer is nickel. When X is bromine, the preferred ion transitional catalyst is palladium. Regardless of the choice of the cacifier, the reaction is carried out, for example, in a suitable solvent solution or in a mixture of Solvenids. The inert solveníes conventionally do not react with the corresponding parfide maerials of the formulas (I I b), (l l l b), and (I I c). A suitable solven for the reaction is an ether solvent, such as ethyl ether, tertiary butyl ether, tetrahydrofuran, butyl ether, 1,2-dimethoxy-ethane, or 1,2-diethoxy-eanine; a bipolar aprolic solution, such as 1-methyl-2-pyrrolidinone (ie, NMP), and 1,3-dime-propyl-3,4,5,6-dihydro-2 (1 H) -pyrimidinone (ie, DMPU) ); an aromatic solution such as ileum or xylene; or a mixture of two or more Solvenis selected from the previous groups. A preferred solution is the hydrohydrofuran. The preferred reaction is carried out at an ambient temperature of -10 ° C and 60 ° C, preferably between 10 ° C and 35 ° C.

As described hereinabove, the present invention provides a process for the preparation of a pro tected 2 '- (1 H -tetrazol-5-yl) -biphenyl-4-carbaldehyde of Formula (I), as exemplified by mediation the following reaction scheme: which comprises coupling a N-propylated phenyl-tetrazole (X = Cl or Br; Y = a propyclic group of iozole), with an aryl-magnesium halide (Hal = Cl, Br, I; Ri , R2 = alkyl of 1 to 10 carbon atoms, or combined are alkylene of 2 to 10 carbon atoms), in the presence of an ion transitional cayalizer, which is a complexed or non-complexed or nickel-supported complex, palladium, plafino, cobalfo, manganese, or copper, or a salt corresponding thereto, and optionally a cayali cal amount of a metal salt additive, such as copper salt (l), copper (ll), zinc salt (l) ), platy (l), cadmium (ll), mercury (ll), aluminum (ll l), gallium (l ll), aluminum (ll l), esfa (IV), titanium (IV), or zirconium (IV), in the presence of an inert solvent or a mixture of inert solveníes.

In a similar manner, the present invention provides a process for the manufacture of a suitable alcohol of Formula (I C) as exemplified by the following reaction scheme: which comprises coupling a N-prolected phenyl-iarazolol (X = Cl or Br; Y = a pro-forcer group of idrazole), with an aryl-magnesium halide (Hal = Cl, Br, I; R3 = a hydroxyl proiector group) ), in the presence of an ion transition catalyst, which is a complexed, non-complexed, or suported nickel, palladium, platinum, cobalt, manganese, or copper, or a corresponding salt thereof, and optionally a canine of a metal salt additive, such as a copper (l), copper (ll), zinc (ll), plate (l), cadmium (ll), mercury (ll) salt, aluminum (III), gallium (III), Indian (III), Spanish (IV), Iphicum (IV), or Zirconium (IV), in the presence of an inert Solvenite or a mixture of inert Solvenids . The preferred Hal is, for example, preferred Br. R-i and R2 are, for example, methyl. Preferred R3 is, for example, 2-terahydro-pyranyl. Preferred X is, for example, Cl. When X is chlorine, a preferred ionization signal catalyst is a nickel (O) or nickel complex (ll), for example, a complex of a nickel salt (II) which it is coordinated by at least one organophosphorus compound containing irivalent phosphorus. Nickel complexes (11) comprising two organophosphorus ligands are preferred. Particularly preferred are nickel complexes (11) with organophosphorus ligands which contain two trivalent phosphorus atoms, such as dichloro- [1,2-bis- (diphenyl-phosphino) -ellan] -nickel (II) ( that is, NiCI2 (dppe)). A preferred metal salt additive is, for example, a zinc salt (1), such as ZnCl 2 and ZnBr 2. The solveníes preferred are solveníes éíéreos, in paríicular tetrahidrofurano.

When X is chloro, the compounds of Formula (I) can be prepared without the metal salt additive (eg, ZnCl2) in the above process, i.e. catalyzing the coupling reaction exclusively by the nickel catalyst. When X is bromine, a preferred ionization metering cathizer is a palladium complex, for example a palladium (O) complex or a palladium salt complex (II) with at least one phosphorus-containing organophosphorus compound. írivaleníe. Palladium complexes (II) comprising two organophosphorus ligands are preferred. Particularly preferred are palladium (II) complexes with organo-phosphorus ligands which contain two groups of highly-active phosphorus, such as dichloro- [1,1 '-bis- (diphenyl-phosphino) -ferrocene] -palladium (II). (that is to say, PdCI2 (dppf)), or its dichloromethane adduct. A preferred metal salt additive is, for example, a zinc salt (1), such as ZnCl 2 and ZnBr 2. In a variation of the present invention, another embodiment of the present invention is a process for the manufacture of a compound of Formula (I): where Y represented a propylene group of leirazole, and Ri and R2, independently of one of the ring, represented alkyl of 1 to 10 carbon atoms, or R-1 and R 2 combined with alkylene form alkylene of 2 to 1 0 carbon atoms; which comprises: (a) reacting a compound of Formula (II a): wherein Hal is chlorine, bromine, or iodine, with an acymal form of magnesium, in an appropriate solvency, (b) reacting an aryl magnesium halide compound resulting from Formula (I I b): in the presence of a transition melal catalyst, with a compound of Formula (II c): wherein X is chlorine, in the absence of a metal salt additive; and if necessary, isolating a compound resulting from Formula (I). Still another variation of the present invention is a process for the manufacture of a compound of the Formula (I C): wherein Y represents a protecting group of terazosol, and R3 represented a proiecfor hydroxyl group; which comprises: (a ') reacting a compound of the Formula (ll l a): wherein Hal is chlorine, bromine, or iodine, with an acrylic form of magnesium, in an appropriate solvent; (b ') reacting an aryl magnesium halide compound resulting from Formula (ll l b): in the presence of a transition metal catalyst, with a compound of Formula (II c): wherein X is chlorine, in the absence of a metal salt additive; and if necessary, isolate a resultant compound of the Formula (I C). A further embodiment of the invention is reaction step (b) or (b '), respectively, that is, the specific reaction of a compound of Formula (II b) or (IIIb), respectively, with a compound of the Formula (II c), wherein X is chloro. In the present reaction, surprisingly, no addition of a catalytically effective amount of a metal salt additive is necessary to result in a compound of Formula (I) or (I C), respectively. In the case where both the salt of the transition metal and the salt of the metal salt are omitted, a significant amount of the compound of the formula (I) or (IC), respectively, is not formed from a starting of the Formula (II c), where X is chlorine.

Isolation Step: Isolation of a compound of Formula (I) or (IC), is carried out according to conventional isolation methods, such as by means of crystallization of the resulfanfe compound of Formula (I) or (IC) ) from the reaction mixture, if desired or necessary after processing, especially by means of excretion, or mediating the chromatography of the reaction mixture, or any combination of methods.

Step (c): For this purpose, groups of a compound resulting from Formula (I) or (IC) of step (b) or (b '), respectively, are removed in sequence or in a single step under conditions of hydrolysis, preferably in the presence of a Bronsted acid. Step (c) is carried out, for example, by dissolving a compound of Formula (I) or (IC) in water or in a mixture of water and an appropriate organic solvent, and subsequently it is added with an acid. , preferably at a high temperature. Suitable organic solvents are alcohols, such as tetrahydrofuran, 1,4-dioxane, butyl ether, nitriles, such as acetonitrile, alcohols, such as melanol, eneol, 1-propanol, 2-propanol, 1-butanol, isopropyl acephalope , Ioluene, xylene, acetic acid, or formic acid. The preferred solvents are methanol and ethanol. Suitable acids are Bronsted acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, ethane sulphonic acid, para-iso-sulfonic acid, benzoic acid, acetic acid, formic acid, as well as the acids of Bronsfed absorbed by polymer (for example, resins for the exchange of acid ions). The preferred acids are sulfuric acid and hydrochloric acid. The acid content used is preferably 0.05 and 2.0 equivalents with respect to a compound of Formula (I) or (I C), more preferably enter 0.1 and 1.2 equivalents. The reaction is carried out at a temperature between 0 ° C and the boiling point of the solvenol, preferably between 25 ° C and 70 ° C. The isolation of a compound resulting from Formula (IA) or (IB) is carried out in accordance with conventional isolation methods, such as by crystallization of a compound of Formula (IA) or (IB) from the reaction mixture, and if desired or necessary, after processing, especially by extraction, or by chromatography of the reaction mixture, or any combination of the same. For example, the crisíalización of the product is carried out mediating the deslilación of all or part of the organic solvent, water is added, the mixture is cooled, or a combination of these measures. In the technique there are several known maíeriales de paríida of the Formulas (I I a) and (I 1 a), and can be prepared according to methods well known in the art. For example, a compound of Formula (I I a) can be obtained by acetylation traced by conventional acid of a 4-halo-benzaldehyde, in the presence of an alcohol or diol. For example, the preparation of the compound of Formula (II a), where Hal is bromine, and Ri and R2 are meyilo, is described in Journal of Organic Chemistry 1991, 56, 4280. The corresponding correspondence in which R- \ and R2 are It can be prepared in ethylene in the presence of oriloform and an acid tracer. A compound of the Formula (II) can be prepared, for example, by means of a conventional acid-caphalized reaction of a 4-halo-benzyl alcohol with a suitable alkylating agent, such as 3,4-dihydro-2H-pyran. For example, the preparation of the compound of the Formula (IIIa), wherein Hal is bromine, and R3 is terahydro-pyran-2-yl, is described in Tetrahedron 1983, 39, 2531. Different starting materials are known in the art. of the Formula (II c) with different protecting groups Y. The preparation of some examples is described in European Patent Number EP 788487. The following Examples illustrate the invention described above; however, they are not intended to limit its scope in any way, for example, to specific reaction conditions.

Example 1: Preparation of 5- (4'-ri, 31-dioxan-2-l-bif in l-2-yl) -2- (1-methyl-1-phenyl) -2H-tetrazole To the magnesium burrs (0.882 grams) are added, under anhydrous conditions, 12 milliliters of a solution of 2- (4-bromo-phenyl) - [1, 3] -dioxane (8.02 grams, 33 millimoles) in anhydrous tefrahydrofuran. (33 milliliters). The mixture is heated to about 50 ° C, and 5 gofas of 1,2-dibromo-yano are added. After the reaction is started, the mixture is heated to reflux, and the remainder of the solution of 2- (4-bromo-phenyl) - [1, 3] -dioxane is added over 40 minutes. The mixture was further stirred at 60 ° C for 1 hour, and finally allowed to cool to ambient temperature. The concentration of the 4 - ([1, 3] -dioxan-2-yl) -phenyl-magnesium bromide in the solution above the excess of magnesium burrs is 0.50 M according to the filtration. In another mafia, dichloro- [1, 3-bis- (diphenyl-phosphino) -propane] -nickel (ll) (0.022 grams, 0.04 millimoles) is suspended in ferbuyl-methyl-ether (3 milliliters) and cooled to Approximately 0 ° C, add a 0.5M solution of zinc chloride in the hydrofuran (0.40 milliliters, 0.20 mmol) and a solution of 5- (2-chloro-phenyl) -2- (1-methyl-1-phenyl- ethyl) -2H-ylerazol (1.20 grams, 4.0 mmol) in ether-methyl-ether-ether (1.2 milliliters). To the suspension is vigorously agitated, add to it, at approximately 0 ° C, 9.6 milliliters of the bromide solution of 4 - ([1, 3] - dioxan-2-yl) -phenyl-magnesium 0.5M lower (4.8 millimoles ) for 1 hour. The resulting dark brown solution is allowed to warm up, and is further stirred at ambient temperature for 20 hours. The mixture is cooled to approximately 0 ° C, quenched with 10 milliliters of a 3.8 percent solution of ammonium chloride in water, and diluted with ethyl acetate (25 milliliters). The aqueous phase is separated and extracted with ethyl acetate (25 milliliters). The combined organic phases are washed with a 0.5M solution of sodium hydroxide in water (10 milliliters), and with a 10 percent solution of sodium chloride in water (10 milliliters). The combined organic phases are evaporated in vacuo. A solution of the pale green solid resulting in a small amount of ethyl acetate is filtered and evaporated. The resulting pale green solid is purified by column chromatography on silica gel, eluting with a 1: 10 mixture of tert-butyl-ether and toluene, to give 5- (4 '- [1,3] -dioxan- 2-yl-biphenyl-2-yl) -2- (1-methyl-1-phenyl-eyl) -2H-tetrazole as colorless crystals. H NMR (400 MHz, d6-DMSO): 1.47-1.52 (m, 1 H), 2.01 (s, 6H), 2.02-2.07 (m, 1 H), 3.96-4.02 (m, 2H). , 4.17-4.21 (, 2H), 5.55 (s, 1 H), 6.95-6.98 (m, 2H), 7.10-7.13 (m, 2H), 7.32-7.39 (m, 5H), 7.51 -7.53 (m, 1 H), 7.56-7.61 (m, 1 H), 7.65-7.69 (m, 1 H), 7.76-7.80 (m, 1 H). Melting range: 102-106 ° C.

Example 2: Preparation of 5- (4'-diethoxy-methyl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-yl) -2H -tetrazo I To the magnesium burrs (2.92 grams) are added, under anhydrous conditions, one fifth of a solution of 1-bromo-4- (dieioxy-methyl) -benzene (25.9 grams, 100 millimoles) in anhydrous hydrohydrofuran (80 milliliters) ). The mixture is heated to about 40 ° C, and 1,2-dibromoethane (0.09 milliliters, 1.0 millimoles) is added. After the reaction is started, the remainder of the solution of 1-bromo-4- (diethoxy-methyl) -benzene is added over 1 hour. The resulting mixture is further agitated at 40 ° C for 2 hours, and at room temperature for 30 minutes, and finally diluted by the addition of anhydrous tetrahydrofuran (25 milliliters). The concentration of 4- (diethoxy-methyl) -phenyl-magnesium bromide in the solution above the excess of the magnesium burrs is 0.46 M according to the titration. In another flask, dichloro- [1,3-bis- (diphenyl-phosphino) -propane] -nickel (11) (0.027 grams, 0.05 mmol) is suspended in tert-butyl ether (3.8 milliliters), and cooled at about 0 ° C, before adding a 0.5M solution of zinc chloride in tetrahydrofuran (0.50 milliliters, 0.25 millimoles), and a solution of a mixture of 5- (2-chloro-phenyl) -2- (fefrahydropyran-2) -yl) -2H-ylerazol and 5- (2-chloro-phenyl) -1 - (tetrahydropyran-2-yl) -1 H-tetrazole (1.32 grams, 5.0 mmol) in tert-butyl methyl ether (1. 3 milliliters). To the resulting vigorously stirred suspension is added, at about 0 ° C, 13 milliliters of the solution of 4- (diethoxy-meityl) -phenyl-magnesium bromide 0.46M above (6.0 mmol) for 1 hour. The resulting black-yellow solution is stirred at approximately 0 ° C for 5 hours, allowed to warm up, and further stirred at ambient temperature for 19 hours. The mixture is cooled to about 0 ° C, and quenched with a 7.5 percent solution of ammonium chloride in water (10 milliliters). The aqueous phase is separated and extracted with ethyl acetate (25 milliliters). The combined organic phases are washed with water (10 milliliters), with a 7.5 percent solution of sodium carbonate in water (10 milliliters), and with a 10 percent solution of sodium chloride in water (10 milliliters). The combined organic phases are evaporated in vacuo. A solution of the brown-yellow oil results in a small amount of ethyl acetate, is filtered and evaporated. The resulting oil (2.68 grams) is purified by column chromatography on silica gel, eluting with a 1: 4 mixture of ethyl acetate and hexane (in the presence of 0.2 percent by volume of triethylamine), to provide the major isomer of (N-isomer) 5- (4'-diethoxy-meityl-biphenyl-2-yl) -2- (terahydro-pyran-2-yl) -2H-tetrazole as a colorless oil. 1H NMR of the N2 isomer (400 M Hz, CDCI3): 1.24 (t, J = 7.2 Hz, 6H), 1.60-1.67 (m, 3H), 1.86-2.03 (m, 2H ), 2.1 1 -2.17 (m, 1 H), 3.50-3.73 (m, 6H), 5.49 (s, 1 H), 5.97-5.99 (m, 1 H), 7.17-7.20 (m, 2H), 7.37 -7.39 (m, 2H), 7.43-7.56 (m, 3H), 7.90-7.92 (m, 1 H).

Example 3: Preparation of 5- (4 '-ri, 31-dioxan-2-yl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-yl) -2H-tetrazole and 5- (4') -ri, 3T-dioxan-2-β-biphenyl-2-yl) -1 - (tetrah idro-pyrn-2-yl) -1 H-tetrazole A suspension of magnesium burrs (2.68 grams) in anhydrous tetrahydrofuran (20 milliliters) is cooled to 10 ° C, and 5 drops of 1,2-dibromo-ethane are added. 2 milliliters of a solution of 2- (4-bromo-phenyl) - [1,3] dioxane (24.3 grams, 100 mmol) in anhydrous tetrahydrofuran (80 milliliters) are added at 10 ° C under vigorous stirring. After the reaction is started, the remainder of the solution of 2- (4-bromo-phenyl) - [1, 3] -dioxane is added for 90 min. The mixture was further stirred at about 16 ° C for 2 hours, and at 25 ° C for 75 minutes. The concentration of the 4 - ([1, 3] -dioxan-2-yl) -phenyl-magnesium bromide in the solution above the excess of magnesium burrs is about 0.90M. In January, dichloro- [1, 3-bis- (diphenyl-phosphino) -propane] -nickel (l 1) (0.054 grams) is suspended.; 0.10 mmol) in 1, 2-dimethoxy-elane (7.7 milliliters), and cooled to approximately 0 ° C, then add a 0.5M solution of zinc chloride in tetrahydrofuran (1.0 milliliters, 0.50 mmol) and a solution of a mixture of 5- (2-chloro-phenyl) -2- (tetrahydropyran-2-yl) -2H-teryrazol and 5- (2-chloro-phenyl) -1 - (tetrahydropyran-2-yl) -1 H -teyrazol (2.65 grams, 10.0 millimoles) in 1,2-dimethoxy-ethane (2.7 milliliters). To the suspension is vigorously agitated, 13.4 milliliters of the solution of 4 - ([1, 3] -dioxan-2-yl) -phenyl-magnesium bromide 0.90 M (12.0 millimoles) are added to it at approximately 0 ° C. last 1 hour. The resulting yellow-brown solution is allowed to warm up, and is further aggravated at ambient temperature for 3 hours. The mixture is cooled to approximately 0 ° C, and quenched with a 7.5 percent solution of ammonium chloride in water (20 milliliters). The aqueous phase is separated and extracted with elyl acetate (50 milliliters). The combined organic phases are washed with water (20 milliliters), with a 7.5 percent solution of sodium carbonate in water (20 milliliters), and water (20 milliliters). The combined organic phases are evaporated in vacuo. A solution of the resulting oil in a small amount of ethyl acetate is filtered and evaporated. The resulting oil is purified by column chromatography on silica gel, eluting with a 1: 2 mixture of acetone and hexane, to provide the major isomer (N-isomer) of 5- (4 '- [1, 3 ] -dioxan-2-yl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-yl) -2H-heerazolol as a colorless acid, and the minor isomer (N-isomer) of 5- (4 '- [1, 3] -dioxan-2-yl-biphenyl-2-yl) -1 - (tetrahydro-pyran-2-yl) -1 H-tetrazole as colorless crystals. 1 H NMR of the N-isomer (400 MHz, CDCl 2): 1.42-1.47 (m, 1 H), 1.57-1.65 (m, 3H), 1.79-1.87 (m, 1 H), 1 .96-2.03 (m, 1 H), 2.10-2.27 (m, 2H), 3.60-3.69 (m, 2H), 3.95-4.01 (m, 2H), 4.23-4.27 (m, 2H) ), 5.48 (s, 1 H), 5.98-6.00 (m, 1 H), 7.18-7.21 (m, 2H), 7.38-7.42 (m, 3H), 7.46-7.54 (m, 2H), 7.89-7.91 (m, 1 H > - 1 H NMR of the N-isomer (400 MHz, CDCl 3): 0.98-1.02 (m, 1H), 1.31-1.36 (m, 1H), 1.42-1.47 (m, 2H), 1.51-1.61 (m, 1H), 1.87-1.96 (m, 2H), 2.14-2.26 (m, 1H), 3.25-3.31 (m, 1H), 3.70-3.75 (m, 1H), 3.93-4.00 (m, 2H), 4.22-4.27 (m , 2H), 4.84-4.87 (m, 1H), 5.45 (s, 1H), 7.12-7.15 (m, 2H), 7.40-7.42 (m, 2H), 7.50-7.68 (m, 4H). Enlarge it by fusion of the N1-isomer: 125-127 ° C.

Example 4: Preparation of 2 '- (1H-tetrazol-5-ill-biphenyl-4-carbaldehyde HaSO ^ HjO / EtOH A suspension of magnesium burrs (6.31 grams) in anhydrous tetrahydrofuran (59 milliliters) was cooled to 14 ° C, brought with a 1M solution of di-isobuyl aluminum hydride in hydrofuran (2.35 milliliters, 2.4 millimoles), and Stir for 20 minutes. At 14 ° C, 1-bromo-4-dimethoxy-meityl-benzene (2.72 grams, 11.7 mmol) is added under vigorous stirring. After the reaction is started, more 1-bromo-4-dimethoxy-methyl-benzene (51.79 grams, 223 mmol) is added for 45 min- utes, while the mixture is diluted with two portions of anhydrous fetrahydrofuran (from 59 milliliters each). The resulting mixture is further stirred at approximately 25 ° C for 2.5 hours. The concentration of the 4- (dimethoxy-methyl) -diphenyl magnesium bromide in the solution above the excess of the magnesium burrs is approximately 1.0m. In another mafraz, a mixture of 5- (2-chloro-phenyl) -2- (feirahydropyran-2-yl) -2H-y-erazolol and 5- (2-chloro-phenyl) -1- (teirahydropyran-2-yl) - 1 H-feyrazol (98.2 percent content, 53.91 grams, 200 mmol), dissolved in anhydrous fefrahydrofuran (37 milliliters) under an inert atmosphere, and dichloro- [1,2-bis] - (diphenylphosphino) ) -ethane] -nickel (ll) (0.862 grams, 1.60 millimoles), and a 0.5M solution of zinc chloride in tetrahydrofuran (6.0 milliliters, 3.0 millimoles). The resulting vigorously stirred suspension is cooled to about 14 ° C, and the solution of 4- (dimethoxymethyl) -phenyl-magnesium bromide 1 .0M above is added. (229 milliliters, 230 millimoles) for 1 hour, while the temperature is maintained below 25 ° C through external cooling. The dark brown reaction mixture is stirred at room temperature for 17.5 hours. After that, more than 99 is converted by half of the parity material, and methanol (8.0 milliliters) is added to the mixture. One of the Solveníes (approximately 156 milliliters) parades under reduced pressure. Ethylene is added (307 milliliters in total), while more Solvenis are paraded. To the resulting brown color mixture, a mixture of a 2M sulfuric acid aqueous solution (32 milliliters, 64 millimoles) and water (75 milliliters) is added at 50 ° C for 10 min. The mixture is further stirred at 50 ° C for 50 minutes, at 60 ° C for 1.5 hours, and at 35 ° C overnight. The mixture is stirred at 60 ° C with activated charcoal (5.3 grams) and filter aid (2.7 grams) for 40 minutes in water, and then filtered at about 55 ° C. The orange colored filtrate is concentrated by means of desilylation of approximately 202 milliliters of the solvents under reduced pressure. After adding water (48 milliliters) at 50 ° C, the resulting stirred suspension was allowed to cool to room temperature overnight, and was further stirred at about 10 ° C for 90 min. The solids are collected by filtration, washed with a 1: 2 mixture of ethanol and water, and with water, and dried under reduced pressure at about 60 ° C, to provide the 2 '- (1 H-tetrazole-5 -yl) -biphenyl-4-carbaldehyde as a pale yellow crystalline solid. Melting range: 188.6-189.9 ° C.

Example 5: Preparation of 5- (4'-diethoxy-methyl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-p-2H-tetrazole To a suspension of magnesium burrs (5.1 1 gram) in anhydrous tetrahydrofuran (40 milliliters), 1,2-dibromo-aeano (0.106 milliliters, 1.2 millimoles) is added. The suspension is cooled to 12 ° C, and 6 milliliters of a solution of 1-bromo-4- (diethoxy-meityl) -benzene (53.6 grams) are added.; 200 millimoles) in anhydrous hydrohydrofuran (120 milliliters), and a second portion of 1,2-dibromo-ethane (0.106 milliliters; 1.2 millimoles). After the reaction is started, the residue of the solution of 1-bromo-4- (diefoxy-methyl) -benzene is added for 90 minutes. The resulting mixture is further agitated from 20 ° C to 25 ° C for 2.5 hours. The mixture is diluted with anhydrous teirahydrofuran to a total volume of 250 milliliters. The concentration of the 4- (diethoxy-methyl) -phenyl magnesium bromide in the solution above the excess of the magnesium burrs is about 0.78 M. In another flask, dichloro- [1,1'-bis- (diphenyl-phosphino) -ferrocene] -palladium (11) dichloro-methane (0.012 grams, 0.01 5 mmol), a solution of sodium chloride, is added to the dichloro-methane adduct. 0.5M zinc in tetrahydrofuran (0.6 milliliter, 0.30 millimole), and a solution of a mixture of 5- (2-bromo-phenyl) -2- (tetrahydropyran-2-yl) -2H-tetrazole and 5- (2-bromine) phenyl) -1- (tefrahydropyran-2-yl) -1 H-felrazol (4.99 g bouquets; 14.3 mmol) in leihydrofuran (30 milliliters). To the yellow-orange solution is agitated, 22.2 milliliters of the above solution of 4- (dieyoxy-methyl) -phenyl-magnesium bromide 0.78M (17.3 millimoles) are added for 2 hours at ambient temperature. The resulting orange solution is further stirred at ambient temperature for 18 hours. After that, no more starting material could be defected by thin layer chromatography. The mixture is cooled to about 0 ° C, and a solution of sodium hydrogen carbonate (2.0 grams) in water (25 milliliters) and ethyl acetate (30 milliliters) is added.

The aqueous phase is separated and extracted with ethyl acetate (40 milliliters). The combined organic phases are washed with a solution of sodium hydrogen carbonate (2.0 grams) in water (25 milliliters), and twice with water (25 milliliters), before being evaporated in vacuo. The resulting orange oil is purified by column chromatography on silica gel, eluting with a mixture of 1: 4 acetyl ether and hexane (in the presence of 0.3 percent by volume of triethylamine), to provide the isomer Main (N-isomer) of 5- (4'-diefoxy-methyl-biphenyl-2-yl) -2- (eeryhydro-pyran-2-yl) -2H-tetrazole, as a pale yellow oil. 1 H NMR of the N-isomer (400 MHz, CDCl 3): 1.24 (t, J = 7.2 Hz, 6H), 1.59-1.67 (m, 3H), 1.85-2.03 (m, 2H), 2.1 1 -2.18 (m, 1 H), 3.50-3.74 (m, 6H), 5.49 (s, 1 H), 5.97-5.99 (m, 1 H), 7.17-7.20 (m, 2H), 7.38-7.40 ( m, 2H), 7.43-7.56 (m, 3H), 7.90-7.92 (m, 1 H).

Example 6: Preparation of 2 '- (1 H-tetrazol-5-yl) -biphenyl-4-carbaldehyde To 5- (4'-diethoxy-meityl-biphenyl-2-yl) -2- (letter hydroxyran-2-yl) -2H-tetrazole (0.408 grams, 1.00 millimoles), 94 percent ethanol is added ( 2.5 milliliters), and a 2N aqueous solution of hydrochloric acid (0.5 milliliters, 1.0 millimoles). The resulting solution is heated at 45 ° C for 3 hours. After the addition of water (approximately 2 milliliters), the mixture is allowed to cool to ambient temperature, and then stirred at 0 ° C to 5 ° C for 30 minutes. The resulting suspension is filtered, and the solids are washed with a small amount of water, and dried under vacuum at 40 ° C, to provide the 2 '- (1 H-tetrazol-5-yl) -biphenyl-4-carbaldehyde like a white crystalline powder. Melting point: 187.5-190.0 ° C.

Example 7: Preparation of 5- (4'-dimethoxy-methyl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-yl) -2H-tetrazole in the presence of a nickel catalyst and in the absence of a zinc salt A suspension of magnesium burrs (2.35 grams) in anhydrous tetrahydrofuran (66 milliliters) is cooled to 14 ° C, treated with a 1 M solution of di-isobutyl aluminum hydride in tetrahydrofuran (1.8 milliliters, 1.8 millimoles); and it shakes during 20 minutes. At 14 ° C, 1-bromo-4-dimefoxy-methyl-benzene (1.02 grams, 4.4 mmol) is added under vigorous stirring. After the reaction is started, more 1-bromo-4-dimethoxy-meityl-benzene (19.32 grams, 83.6 millimoles) is added for 50 minutes. The resulting mixture is further stirred at about 25 ° C for 2.5 hours. The concentration of 4- (dimethyloxymethyl) -phenyl-magnesium bromide in the solution above the excess of the magnesium burrs is about 0.96M. In another flask, a mixture of 5- (2-chloro-phenyl) -2- (ε-hydrohydropyran-2-yl) -2H-feadrazole and 5- (2-chloro-phenyl) -1- (tetrahydropyran-2-yl) -1 H-teyrazolol (94% content, 4.22 grams; . 0 mmol), dissolve in anhydrous hydrohydrofuran (2.8 milliliters) under an inert atmosphere, and add dichloro- [1,2-bis- (diphenyl-phosphino) -elane] -nickel (ll) (80.8 milligrams, 0.15 millimoles) . The suspension was vigorously stirred until cooled to approximately 15 ° C, and the above solution of 4- (dimethyloxymethyl) phenylmagnesium 0.96M (18 milliliters; 17.3 mmol) was added for 1 hour, while The temperature is maintained below 25 ° C by means of exotherm cooling. The dark brown reaction mixture is stirred at room temperature for 22.5 hours. After that, approximately 94 percent of the starting material is converted. Methanol (1.2 milliliters, 30 millimoles) is added to the mixture, followed by isopropyl acetate (35 milliliters), a solution of ammonium chloride (0.4 grams) in water (10 milliliters), and water (10 milliliters). The layers are separated. The organic layer is washed with water (10 milliliters), three times with a solution of sodium hydrogen carbonate (1.0 grams) in water (12 milliliters), and twice with water (10 milliliters), then evaporated in vacuo. The resulting brown oil is purified by column chromatography on silica gel, eluting with a 1: 4 mixture of ethyl acetate and hexane (in the presence of 0.3 percent by volume of triethylamine), to provide the major isomer (N2-isomer) of 5- (4'-dimethoxy). methyl-biphenyl-2-yl) -2- (ephehydro-pyran-2-yl) -2H-y-erazolol, as a pale yellow oil. 1 H NMR of the N-isomer (400 M Hz, CDCl 3): 1.59-1.68 (m, 3H), 1.86-1.93 (m, 1 H), 1.96-2.04 (m, 1 H), 2.12-2.20 (m, 1 H), 3.34 (s, 6H), 3.65-3.76 (m, 2H), 5.38 (s, 1 H), 5.95-5.98 (m, 1 H), 7.18- 7.21 (m, 2H); 7.36-7.38 (m, 2H), 7.44-7.56 (m, 3H), 7.90-7.92 (m, 1 H).

Example 8 I ntent for the preparation of 5- (4'-dimethoxy-methyl-biphenyl-2-yl) -2- (tetrahydro-pyran-2-yl) -2H-tetrazole in the absence of a catalyst A mixture of 5- (2-chloro-phenyl) -2- (teirahydro-pyran-2-yl) -2H-y-erazolol and 5- (2-chloro-phenyl) -1- (eiirahydropyran-2-yl) -1 Hyaline (94 percent content, 4.22 grams, 15.0 millimoles, the same batch as used in Example 7), is dissolved in anhydrous water (2.8 milliliters) under an inert atmosphere. The vigorously agitated suspension is cooled to approximately 15 ° C, and a solution of 4- (dimethoxy-methyl) -phenyl-magnesium bromide 0.96M (1 8 milliliters, 17.3 millimoles, the same batch as used in the former) is added. Example 7) for 1 hour, while keeping the temperature below 25 ° C by external cooling. The brown reaction mixture is stirred at ambient temperature for 22 hours. After that, the HPLC analysis is performed on a sample which, as usual, is hydrolyzed with dilute aqueous hydrochloric acid. The analysis shows mainly non-converted parenteral material (detected as 5- (2-chloro-phenyl) -1H-teyrazol), and less than 0.25 per area of CC coupling product (detected as 2 '- (1 H -ephrazol-5-yl) -biphenyl-4-carbaldehyde). Finally, when methanol (1.2 milliliters, 30 millimoles) is added to the mixture, an unusually strong exotherm is observed, which indicates that most of the 4- (dimethoxy-meityl) -phenyl-magnesium bromide is still present after a total reaction time of 23 hours.

Example 9: Preparation of 2- (tetrahydro-pyran-2-yl) -5-r4 '- (tetrahydro-pyran-2-yloxy-methyl) -b-phenyl-2-p-2H-tetrazole ZnClj (cat.) A suspension of magnesium burrs (0.48 grams) in anhydrous terahydrofuran (13.5 milliliters) was cooled to 14 ° C, brought with a 25 weight percent solution of diisobutyl aluminum hydride in toluene (0.24 milliliters; millimoles), and stirred for 20 minutes. At 14 ° C, 2- (4-bromo-benzyloxy) -tetrahydropyran (94.5 percent confenide, 0.26 grams, 0.90 millimole) is added under vigorous stirring. After the reaction is started, more 2- (4-bromo-benzyloxy) -etrahydropyran (94.5 percent content, 4.91 grams, 17.1 mmol) is added for 40 minutes. The resulting mixture is further stirred at about 25 ° C for 2.5 hours. The theoretical concentration of 4- (tephrahydro-pyran-2-yloxy-methyl) -phenyl-magnesium bromide in the solution above the excess of magnesium burrs is approximately 0.95M. In another flask, a mixture of 5- (2-chloro-phenyl) -2- (tetrahydropyran-2-yl) -2H-teryrazol and 5- (2-chloro-phenyl) -1 - (teirahydropyran-2-yl) - 1 H-tetrazole (content of 94 percent, 4.22 grams, 15.0 mmol), dissolve in anhydrous terahydrofuran (2.8 milliliters) under an inert atmosphere, and add dichloro- [1,2-bis- (diphenyl-phosphine) -ethane] -nickel (ll) (80.8 grams, 0.15 millimoles), and a 0.5M zinc chloride solution in fefrahydrofuran (0.45 milliliters, 0.23 millimoles). The resulting vigorously stirred suspension is cooled to approximately 15 ° C, and the solution of 4- (1-hydrohydropyran-2-yloxymethyl) -phenyl-magnesium bromide (19 milliliters, 18 mmol) is added over 1 hour, while It maintains the temperature below 25 ° C by external cooling. The brown reaction mixture is stirred at ambient temperature for 17.5 hours. After that, approximately 97 percent of the parent material is converted according to the HPLC analysis. Methanol (1.2 milliliters, 30 millimoles) is added to the mixture, followed by isopropyl acetate (40 milliliters), a solution of ammonium chloride (0.4 grams) in water (10 milliliters), and water (10 milliliters). The layers are separated. The organic layer is washed with water (10 milliliters), and three times with a solution of sodium hydrogen carbonate (1.0 grams) in water (12 milliliters). The aqueous layer is extracted with isopropyl acetate (50 milliliters). The combined organic layers are washed twice with water (10 milliliters), and evaporate in vacuum. The greenish oil was purified by column chromatography on silica gel, eluting with a 1: 4 mixture of ethyl acetate and hexane (in the presence of 0.3 percent by volume of triethylamine), to provide the main isomer (N-isomer) 2- (tetrahydro-pyran-2-yl) -5- [4 '- (terahydro-pyran-2-yloxy-methyl) -biphenyl-2-yl-2H-tetrazole as a colorless oil . Mass spectrum (ESI +): m / z = 421 [M + H] + and m / z = 438 [M + NH4] +.

Example 10: Preparation of r2 '- (1 H-tetrazol-5-yl) -b-phenyl-4-p-methanol 2- (Tetrahydro-pyran-2-yl) -5- [4 '- (tetrahydro-pyran-2-yloxy-methyl) -biphenyl-2-yl] -2H-tefrazol (3.36 grams, 8.00 mmol), they add ethanol to 94 percent (12 milliliters), and a 2M aqueous solution of sulfuric acid (1.0 milliliters, 2.0 millimoles). The resulting mixture was heated at 45 ° C for 3.5 hours. Water is added slowly (16 milliliters), and the mixture is allowed to cool to ambient air. The pH of the reaction mixture was adjusted to a pH of 2 to 3 by the addition of an aqueous solution of 2M sodium hydroxide (0.6 milliliter). The mixture is concentrated under reduced pressure, diluted with isopropyl acetylate (15 milliliters), and washed three times with water (3 milliliters). The organic extrac- tion is concentrated under reduced pressure to a volume of about 4 milliliters, and tert-butyl methyl ether (8 milliliters in total) is slowly added. The mixture is stirred overnight, diluted with a small amount of isopropyl acetate, and further stirred for 4.5 hours. The suspended white solid is filtered, washed with a small amount of isopropyl acetate, and dried under reduced pressure, to give [2 '- (1 H -etrazol-5-yl) -biphenyl-4-yl] - methanol The filtrate is concentrated under reduced pressure, and terbuyl-methyl-ether (3 milliliters) and heptane (0.5 milliliters) are added slowly. The mixture is stirred at room temperature overnight, and from 0 ° C to 5 ° C for 1 hour. The suspended white solid is filtered, washed with a small amount of isopropyl acetate, and dried under reduced pressure, to provide a second crop of [2 '- (1 H -etrazol-5-yl) -biphenyl-4- il] -meanol. I níervalo of fusion: 1 32.4-134.6 ° C.

Example 1 1: Preparation of 2 '- (1 H-tetrazol-5-yl) -bifen il-4-carbaldehyde A mixture of [2 '- (1 H-tefrazol-5-yl) -biphenyl-4-yl] -methanol (1.03 grams, 4.0 mmol), ithylamine (2.80 ml, 20 mmol) and thyl sulfoxide (2 milliliters) ), it is cooled to 12 ° C, and a solution of sulfur dioxide-pyridine complex (1.27 grams, 8.0 mmol) in thylsulfoxide (6.4 milliliters) is added for 10 min. The resulting transpar- en solution is stirred at room temperature for almost 48 hours, during which time more amyrylamine (0.28 milliliters, 2.0 millimoles) is added. The mixture is diluted with ethyl acetate (10 milliliters), cooled from 0 ° C to 5 ° C, and brought slowly with an aqueous 2M hydrochloric acid solution (15 milliliters). The aqueous layer is separated and extracted with ethyl acetate (10 milliliters). The combined organic layers are diluted with ethyl ether (10 milliliters), washed with an aqueous 2M hydrochloric acid solution (15 milliliters), twice with an aqueous solution of 1 M hydrochloric acid (10 milliliters), and with a solution water at 10 percent sodium chloride (10 milliliters). The organic extract is concentrated at 45 ° C under reduced pressure, to a volume of about 4 to 5 milliliters. The slurry was stirred at ambient temperature for 45 minutes, and from 0 ° C to 5 ° C for 1 hour, before filtering. The solids are washed with cold ethyl acetate (2 milliliters), and dried at 45 ° C under reduced pressure, to give the 2 '- (1 H-leyrazol-5-yl) -biphenyl-4-carbaldehyde as a solid. white crystalline. A second crop can be obtained by concentrating the mother liquor to a volume of approximately 1 milliliter, and filtering the solid formed. Melting interval: 1 88.2-189.3 ° C.

Claims (39)

1. CLAIMS 1 . A process for the manufacture of a compound of the Formula (I): wherein Y represented a tefrazol-producing group, and R-, and R2, independently of one another, represent alkyl of 1 to 10 carbon atoms, or R ^ and R2 combined together form alkylene of 2 to 10 carbon atoms; which comprises: reacting a compound of aryl magnesium halide of the Formula (II b): wherein Hal is chlorine, bromine, or iodine, in the presence of an ionization metering device and an effective chemical element of a metal salt additive, with a compound of the Formula (I I c): wherein X is a substituent which, when linked to a phenyl ring, is not substantially replaceable at ambient temperature by an aryl magnesium halide reactant of the Formula (I I b) in the absence of a cafalizer; and if necessary, isolating a compound resulting from Formula (I).
2. 2. A process according to claim 1, wherein an aryl magnesium halide reagent of the Formula (I I b) is prepared by the reaction of a compound of the Formula (I I a): wherein R-,, R2, and Hal have the meanings defined in claim 1, with an active form of magnesium, in an appropriate solvent.
3. 3. A process according to claim 1 or 2, which process further comprises deprotecting a compound of Formula (I), to provide a compound of Formula (I A):
4. 4. A process according to any one of claims 1 to 3, wherein the variable Y is selected from the group consisting of 1-buxidoxy-yl, 1-eioxy-ethyl, 2-yrahydro-pyranyl, and 2-tetrahydro- f uranyl.
5. 5. A process according to any one of claims 1 to 4, wherein an ion transition catalyst is a complex of an ionization meinhal or a cross-ional salt, and 1, 2, or up to 4 coordination ligands selected at from the group consisting of ρ-phenyl-phosphine, γ- (uro-yl-yl) -phosphine, tri- (para-yl) -phosphine, frimethyl-phosphine, chrylo-phosphine, urea-phosphine, tri- (1,1-dimethyl) -ethyl) -phosphine, tricyclo-pentylphosphine, tricyclo-hexyl phosphine, trimethyl-phosphite, triethyl-phosphite, tri- (l -methyl-ethyl) -phosphyl, tricyclo-pentyl-phosphite, tricyclo-hexyl- phosphite, 1,2-bis- (diphenylphosphino) -ethane, 1,3-bis- (diphenyl-phosphino) -propane, 1,4-bis- (diphenyl-phosphino) -butane, 1, -bis- ( diphenyl-phosphino) -ferrocene, 1,1 '-bis- (di-2-propyl] -phosphino) -ferrocene, 1, -bis- [di-diglyl-phosphino) -ferrocene, 1,2-bis- (diphenyl-phosphino) ) -benzene, 2,2'-bis- (diphenyl-phosphino) -1, 1'-biphenyl, 2,2'-bis- (diphenyl-phosphino) -1, 1'-biphenyl, bis- (2-diphenyl) -phosphine-phenyl) -ether, and 9,9-dimethylamino-4,5-bis- (diphenyl-phosphino) -xanthene.
6. 6. A process according to claim 5, wherein a transition me- fa salt is selected from the group consisting of nickel chloride (ll), nickel bromide (ll), and nickel acetyl- acetone (II). ).
7. 7. A process according to claim 5, wherein a transition metal calyser is selected from the group consisting of dichloro-bis- (triphenyl-phosphine) -nickel (II), dichloro- [1,2- bis- (diphenylphosphino) -ethane] -nickel (II) and dichloro- [1,3-bis- (diphenyl-phosphino) -propane] -nickel (II).
8. 8. A process according to claim 5, wherein a transition metal salt is selected from the group consisting of palladium chloride (11), palladium bromide (11), and palladium acellium (11).
9. 9. A process according to claim 5, wherein a transient mealalizer is selected from the group consisting of dichloro-bis- (triphenyl-phosphine) -palladium (II), dichloro- [1, 3] bis- (diphenylphosphino) -propane] -palladium (II), and dichloro- [1, -bis- (diphenyl-phosphino) -ferrocene] -palladium (II), or a dichloromethane adduct thereof.
10. 10. A process according to any of claims 1 to 9, wherein a metal salt additive is selected from the group consisting of a copper salt (l), copper (ll), zinc (ll), silver (l), cadmium (ll), mercury (ll), aluminum (lll), gallium (lll), indium (lll), tin (IV), lithium (IV), and zirconium (IV). eleven .
11. A process according to claim 10, wherein the amount of the metered salt additive is between 0.1 and 8 mole percent relative to a compound of the Formula (I I c).
12. 12. A process according to any of claims 1 to 5, wherein X is chlorine; and an ion transition metal catalyst is a nickel (O) complex, or a nickel salt complex (11) with at least one organophosphorus compound containing trivalenic phosphorus; or an ransition metal catalyst is a nickel complex (11) with an organophosphorus ligand containing two trivalent phosphorus atoms.
13. 13. A process according to claim 12, wherein an ion transition melamine is dichloro- [1,2-bis- (diphenyl-phosphino) -ethane] -nickel (l l); and a metal salt additive is ZnCl2 or ZnBr2.
14. 14. A process according to any of claims 1 to 5, wherein X is bromine; and an ransition metal catalyst is a palladium (O) complex, or a complex of a palladium salt (1) with at least one organo-phosphorus compound that contains urea phosphorus; or an ransition metering device is a palladium complex (1) with an organophosphorus ligand which contains two trivalent phosphorus atoms.
15. 15. A process according to claim 14, wherein a transition metal catalyst is dichloro- [1,1'-bis- (diphenylphosphino) -ferrocene] -palladium (II), or a dichloro- methane thereof; and a metal salt additive is ZnCl2 or ZnBr2.
16. 16. A process according to any of claims 1 to 4, wherein an ion transition catalyst is a non-complexed me chanalizing mehal which is selected from the group consisting of nickel, palladium, platinum, cobalp, manganese, or copper; or wherein a transition metal catalyst is a non-complexed ionization salt which is selected from the group consisting of nickel (ll), palladium (ll), platinum (ll), cobalt (ll), manganese ( ll), copper (ll), or copper (ll), or chloride, bromide, iodide, hydroxide, oxide, acetyl, hydroxy- • acetate, propionate, succinate, urea fluoride, acetyl-acetylonate, nitrate, cyanide, sulphate , trifluoro-mene-sulfonate, methane sulfonate, benzene sulfonate, or p-toluene sulfonate thereof.
17. 17. A process for the manufacture of a compound of Formula (I): wherein Y represents a tetrazole group, and R-, and R2, independently of one another, represent alkyl of 1 to 10 carbon atoms, or Ri and R2 combined together form alkylene of 2 to 10 carbon atoms; which comprises: (a) reacting a compound of the Formula (II a): wherein Hal is chlorine, bromine, or iodine, with an active form of magnesium in an appropriate solvent; (b) reacting a compound of aryl magnesium halide of the formula (I I b): in the presence of an indexing device, with a compound of the formula (I I c): (H e), wherein X is chlorine, in the absence of a metal salt additive; and if necessary, isolating a compound resulting from Formula (I).
18. 18. A process according to claim 17, wherein a transitional me- chanalizer is a nickel (O) complex, or a nickel salt complex (ll) with at least one phosphorus-containing organophosphorus compound. trivalenfe; or a transitional meaal marker is a nickel complex (1) with an organophosphorus ligand containing two trivalent phosphorus atoms.
19. 19. A process for the manufacture of the compound of Formula (I C): wherein Y represents a protecting group of terazosol, and R3 represents a hydroxyl protecting group; which comprises reacting an aryl magnesium halide compound of the Formula (III b): wherein Hal is chloro, bromo, or iodo, in the presence of a transition metal catalyst and a catalytically effective amount of a metal salt additive, with a compound of the Formula (I I c): (H e), wherein X is a substituent, which, when linked to a phenyl ring, is not substantially replaceable at room temperature by an aryl magnesium halide reagent of Formula (III b) in the absence of a catalyst; and if necessary, isolating a compound resulting from Formula (I C).
20. 20. A process according to claim 19, wherein an aryl magnesium halide reactive of the Formula (11) is prepared by the reaction of a compound of the Formula (11): wherein R3 and Hal have the meanings defined in claim 19, with an acivive form of magnesium in an appropriate solvency. twenty-one .
21. A process according to claim 19 or 20, which process further comprises deprotecting a compound of the Formula (I C), to provide a compound of the Formula (I B):
22. 22. A process according to claim 21, which process further comprises treating a compound of the Formula (IB) with an oxidizing agent, in the presence of a suitable solvent, to provide a compound of the Formula (IA):
23. 23. A process according to any of claims 1 to 22, wherein the variable Y is selected from the group consisting of 1-budoxy-ethyl, 1-efoxy-ethyl, 2-tetrahydro-pyranyl, and 2-fetrahydro-furanyl .
24. 24. A process according to any of claims 19 to 23, wherein a transition metal catalyst is a complex of a transition metal or a transition metal salt, and 1, 2, or up to 4 coordination ligands. selected from the group consisting of triphenyl-phosphine, tri- (orfo-yl) -phosphine, tri- (para-yl) -phosphine, trimethyl-phosphine, trieylyl-phosphine, tributyl-phosphine, tri- (1, 1) -dimethyl-efil) -phosphine, tricyclo-pentyl-phosphine, tricyclo-hexyl-phosphine, dimethyl-phosphoryl, tricyclic-phosphyl, tri- (l-methyl-ethyl) -phosphine, tricyclo-pentyl-phosphoryl, tricyclo-hexyl- phosphite, 1,2-bis- (diphenylphosphino) -ethane, 1,3-bis- (diphenyl-phosphino) -propane, 1,4-bis- (diphenyl-phosphino) -butane, 1,1 '-bis - (diphenyl-phosphino) -ferrocene, 1,1 '-bis- (di-2-propyl] -phosphino) -ferrocene, 1,1' -bis- [diterbutyl-phosphino) -ferrocene, 1, 2-bis- (diphenyl-phosphino) -benzene, 2,2'-bis- (diphenyl-phosphino) -1, 1'-biphenyl, 2,2'-bis- (diphenyl-phosphino) -1, 1'-biphenyl, bis- (2- diphenyl-phosphino-phenyl) -ether, and 9,9-dimethyl-4,5-bis- (diphenyl-phosphino) -xaniene.
25. 25. A process according to claim 24, wherein an ion transition salt is selected from the group consisting of nickel chloride (ll), nickel bromide (ll), and nickel acetyl-acetylonate (ll). ).
26. 26. A process according to claim 24, wherein an ion transition caulifold is selected from the group consisting of dichloro-bis- (phenyl-phosphine) -nickel (ll), dichloro- [1,2-] bis- (diphenylphosphino) -yene] -nickel (ll), and dichloro- [1,3-bis- (diphenyl-phosphino) -propane-nickel (ll).
27. 27. A process according to claim 24, wherein a transition metal salt is selected from the group consisting of palladium chloride (II), palladium bromide (II), and palladium acetate (II).
28. 28. A process according to claim 24, wherein a transition metal catalyst is selected from the group consisting of dichloro-bis- (triphenyl-phosphine) -palladium (II), dichloro- [1,3-] bis- (diphenylphosphino) -propane] -palladium (II), and dichloro- [1, -bis- (diphenyl-phosphino) -ferrocene-palladium (11), or a diclucro-methane adduct thereof.
29. 29. A process according to any of claims 19 to 28, wherein a meifal salt additive is selected from the group consisting of a copper (l), copper (ll), zinc salt (l) salt. ), silver (l), cadmium (ll), mercury (ll), aluminum (lll), gallium (lll), indium (lll), tin (IV), titanium (IV), and of zirconium (IV).
30. 30. A process according to claim 29, wherein the amount of the mead salt salt additive used is between 0.1 and 8 molar percent in relation to a compound of Formula (ll c).
31. 31. A process according to any of claims 1 to 5, wherein X is chlorine; and an ion transition catalyst is a nickel (O) complex, or a nickel salt complex (11) with at least one organophosphorus compound containing trivalent phosphorus; or an ransition metal catalyst is a nickel complex (11) with an organophosphorus ligand containing two trivalent phosphorus atoms.
32. 32. A process according to claim 31, wherein a transition metal catalyst is dichloro- [1,2-bis- (diphenyl-phosphino) -ethane] -nickel (ll); and a metal salt additive is ZnCl2 or ZnBr2.
33. 33. A process according to any of claims 19 to 24, wherein X is bromine; and a transition metal catalyst is a palladium (O) complex, or a complex of a palladium salt (II) with at least one organophosphorus compound containing trivalent phosphorus.; or an ionization metering device is a palladium complex (1) with an organophosphorus ligand containing two trivalent phosphorus atoms.
34. 34. A process according to claim 33, wherein a transition metal catalyst is dichloro- [1,1'-bis- (diphenyl-phosphino) -ferrocene] -palladium (II), or a dichloro adduction. meíano of the same; and a metal salt additive is ZnCl2 or ZnBr2.
35. 35. A process according to any of claims 19 to 23, wherein a transition metal catalyst is a non-complexed transition medium that is selected from the group consisting of nickel, palladium, platinum, cobalt, manganese, or copper; or wherein a transition metal catalyst is a non-complexed transitional meal salt which is selected from the group consisting of nickel (ll), palladium (ll), platinum (ll), cobalt (ll), manganese ( ll), copper (ll), or copper (ll), or chloride, bromide, iodide, hydroxide, oxide, acetate, hydroxy-acetamide, propionate, succinate, trifluoro-acetate, acetyl-acetonate, nitrate, cyanide, sulfate, trifluoro-methane sulfonate, methane sulfonate, benzenesulfonate, or p-toluene sulfonate thereof.
36. 36. A process for the manufacture of the compound of the Formula (I): wherein Y represents a tetrazole protecting group, and R3 represents a hydroxyl protecting group; which comprises: (a ') reacting a compound of the Formula (11): where Hal is chlorine, bromine, or iodine, with an aciivalent form of magnesium in an appropriate solvency; (b ') reacting an aryl magnesium halide compound resulting from Formula (11b): (flt) in the presence of a transition metal catalyst, with a compound of the Formula (ll c): wherein X is chlorine, in the absence of a metal salt additive; and if necessary, isolating a compound resulting from the Formula (1 C).
37. 37. A process according to claim 36, wherein a transition metal catalyst is a nickel (O) complex, or a nickel salt complex (II) with at least one organophosphorus compound containing iridium phosphorus; or a transitional meaal marker is a nickel complex (II) with an organo-phosphorus ligand containing two ferric acid phosphorus atoms.
38. 38. A compound of the Formula (I C): where Y represented a proiecfor group of feyrazol, and R3 represents a hydroxyl-forming group.
39. 39. A compound according to claim 38, wherein Y and R3, independently of one another, are 1-butoxy-ylyl, 1-eioxy-ylyl, 2-ephhydro-pyranyl, or 2-teirahydro-furanyl.