WO2005014560A1 - A process for the preparation of phenyltetrazole derivatives - Google Patents

A process for the preparation of phenyltetrazole derivatives Download PDF

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Publication number
WO2005014560A1
WO2005014560A1 PCT/EP2004/008576 EP2004008576W WO2005014560A1 WO 2005014560 A1 WO2005014560 A1 WO 2005014560A1 EP 2004008576 W EP2004008576 W EP 2004008576W WO 2005014560 A1 WO2005014560 A1 WO 2005014560A1
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Prior art keywords
formula
compound
phenyl
methyl
tetrazol
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PCT/EP2004/008576
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French (fr)
Inventor
Graziano Castaldi
Pietro Allegrini
Gabriele Razzetti
Alberto Bologna
Marcello Rasparini
Vittorio Lucchini
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Dipharma S.P.A.
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Priority claimed from ITMI20031638 external-priority patent/ITMI20031638A1/en
Priority claimed from ITMI20040929 external-priority patent/ITMI20040929A1/en
Priority to EP04763657A priority Critical patent/EP1660463B1/en
Priority to DE602004010530T priority patent/DE602004010530T2/en
Priority to DK04763657T priority patent/DK1660463T3/en
Priority to JP2006522299A priority patent/JP2007501770A/en
Application filed by Dipharma S.P.A. filed Critical Dipharma S.P.A.
Priority to PL04763657T priority patent/PL1660463T3/en
Priority to MXPA06001485A priority patent/MXPA06001485A/en
Priority to CA002534892A priority patent/CA2534892A1/en
Priority to US10/567,492 priority patent/US7385062B2/en
Publication of WO2005014560A1 publication Critical patent/WO2005014560A1/en
Priority to NO20060603A priority patent/NO331810B1/en
Priority to IL173582A priority patent/IL173582A0/en
Priority to HK07101466A priority patent/HK1094575A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/02—Magnesium compounds

Definitions

  • the present invention relates to a process for the preparation of substituted phenyltetrazole compounds, useful as intermediates for the preparation of angiotensin II antagonists.
  • Angiotensin II antagonists are used, for example, in the treatment of hypertension, anxiety, glaucoma and heart failure.
  • a number of these compounds are characterized by a biphenyltetrazole moiety and can be represented by the following formula (I)
  • Z is an optionally substituted heterocycle containing at least one nitrogen atom; or an amido residue.
  • the residue Z has the following meanings, which identify specific angiotensin II antagonists: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl (losartan); 2-ethoxy-7-carboxy- 1 H-benzimidazol- 1 -yl (candesartan); 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl (irbesartan); and (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoylamino (valsartan).
  • Key intermediates for the preparation of compounds of formula (I) are 2-substituted phenyltetrazoles of formula (II)
  • R is hydrogen, a protecting group or a salifying group and Y is a -B(OR ) 2 group, wherein each R 4 is independently hydrogen or C ⁇ -C 6 alkyl; or a ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine.
  • R is hydrogen, a protecting group or a salifying group and Y is a -B(OR ) 2 group, wherein each R 4 is independently hydrogen or C ⁇ -C 6 alkyl; or a ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine.
  • a number of processes for the preparation of the compounds of formula (II) are known.
  • the process disclosed in US 5,039,814 or in WO 93/10106 comprises the ortho-litiation of the phenyltetrazole and the subsequent transmetallation reaction.
  • the main drawbacks of said process resides in the need to use an organo-lith
  • R is hydrogen, a protecting group or a salifying group and Y is a -B(OR 4 ) 2 group, in which each R 4 is independently hydrogen or Ci-C ⁇ alkyl; or a -ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine; which comprises the reaction of a compound of formula (V)
  • R is as defined above and R 2 and R 3 , which can be the same or different, are straight or branched C ⁇ -C 6 alkyl, C -C 6 cycloalkyl, trialkylsilyl, or R 2 and R 3 , taken together with the nitrogen atom they are linked to, form a saturated, optionally substituted, heterocyclic ring, containing one to two further heteroatoms independently selected from nitrogen, oxygen and sulfur; either with a compound of formula (VI) ZnX 2 (VI) wherein X is as defined above; or with a compound of formula (Via) B(OR' 4 ) 3 (Via) wherein each R' 4 is independently C C 6 alkyl, and, if desired, the subsequent hydrolysis of the resulting boronic ester of formula (II).
  • protecting group R means a tetrazole ring protecting group known in the art, preferably a straight or branched Ci-C ⁇ alkyl, optionally substituted with one or more phenyl groups, in their turn optionally substituted, for example with C 1 -C 4 alkoxy or C C alkylthio.
  • Preferred examples of R are tert-butyl, para-methoxybenzyl, trityl and 1 -methyl- 1- phenylethyl, the latter being particularly preferred.
  • alifying group R means, for example, an alkali or alkaline- earth metal, preferably sodium, potassium or magnesium, more preferably sodium.
  • R 2 and R 3 are C ⁇ -C 6 alkyl groups, they are preferably C 3 -C 6 alkyl groups, more preferably isopropyl, sec-butyl, tert-butyl, most preferably isopropyl.
  • R 2 and R 3 are C 3 -C 6 cycloalkyl groups, they are preferably cyclopentyl and cyclohexyl.
  • R 2 and R 3 are trialkylsilyl groups, they are preferably trimethylsilyl.
  • R is a CpCg alkyl group, it is preferably a straight or branched C 1 -C 4 alkyl group, more preferably methyl, ethyl propyl, isopropyl, sec-butyl, tert-butyl, most preferably methyl, ethyl or isopropyl.
  • heterocyclic ring as defined above preferably means piperidine, piperazine, morpholine, pyrrolidine, more preferably 2,2,6,6- tetramethy lpiperidine .
  • reaction of a compound of formula (V) with a compound of formula (VI) or (Via) is typically carried out in an ether solvent, preferably ethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof, or mixtures thereof with apolar solvents, preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran.
  • apolar solvents preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran.
  • the stoichiometric ratio of a compound of formula (VI) or (Via) to a compound of formula (V) ranges from approx. 1.0 to approx.
  • reaction preferably from 1.1 to 3.0.
  • the reaction is carried out at a temperature ranging from about 20°C to the reflux temperature of the reaction mixture. Reaction times depend on the temperature and the progress of the reaction is monitored by conventional analytical methods.
  • the hydrolysis of a boronic ester of formula (II) to obtain a corresponding compound of formula (II) in which R is hydrogen can be carried out according to known methods, for example by addition of a mineral or organic acid, in particular phosphoric, hydrochloric or acetic acid, to the reaction mixture.
  • the compounds of formula (V) are novel and are a further object of the present invention.
  • Preferred examples of compounds of formula (V) are: • 2-[2-t-butyl-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; • 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; and • 2- [2-(l -methyl- 1 -phenyl-ethyl)-2H-tetrazol- 5 -yl] -phenyl magnesium diisopropylamide, in particular the latter.
  • Compounds (V) can be prepared by reaction of compounds of formula
  • reaction between a compound of formula (III) and a compound of formula (VII) is typically carried out in an ether solvent, for example ethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof, or mixtures thereof with apolar solvents, preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran.
  • ether solvent for example ethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof, or mixtures thereof with apolar solvents, preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran.
  • the stoichiometric ratio of a compound of formula (VII) to a compound of formula (III) ranges from approx. 0.5 to approx. 3.0, preferably from 1.0 to 2.0.
  • the reaction is carried out at a temperature ranging from about 20°C to the reflux temperature of the reaction mixture, preferably at the reflux temperature. Reaction times depend on the temperature, and the progress of the reaction is monitored by conventional analytical methods.
  • the resulting compound of formula (V), which can optionally be isolated, is then reacted with a compound of formula (VI) or (Via).
  • the compounds of formula (VII) can be obtained according to known processes, for example as described in DE 100 61 317. Preferably, the resulting compounds of formula (VII) are reacted with compounds of formula (III) without being isolated.
  • a further object of the invention is the use of a compound of formula (V) for the preparation of a compound of formula (I)
  • a compound of formula (V) is used for the preparation of a compound of formula (I) in which Z is selected from: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl; 2-ethoxy-7-carboxy- 1 H-benzimidazol- 1 -yl; 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl and (S)-N-( 1 -carboxy-2-methy lprop- 1 -yl)-N-pentanoylamino, most preferably 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl.
  • Example 1 Preparation of 2-[2-(l-methyI-l-phenyl-ethyl)-2H- tetrazol-5-yl] -phenyl zinc chloride (II) A mixture of 2-(l -methyl- 1-phenyl-ethyl)- 5 -phenyl-2H-tetrazole (5.0 g;
  • Example 2 Preparation of 2- [2-Trityl-2H-tetrazol-5-yl] -phenyl magnesium diisopropylamide (V) A mixture of l-trityl-5-phenyl-2H-tetrazole (7.9 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. ⁇ -NMR analysis, after treatment with deuterated water, evidences a
  • Example 3 Preparation of 2- [2-t-butyl-2H-tetrazol-5-yl] -phenyl magnesium diisopropylamide (V) A mixture of l-t-butyl-5-phenyl-2H-tetrazole (4.1 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. ⁇ -NMR analysis, after treatment with deuterated water, evidences a 75% conversion to organo-magnesium.
  • Example 4 Preparation of 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide (V) A mixture of 5-phenyl-2H-tetrazole sodium salt (3.4 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. -NMR analysis, after treatment with deuterated water, evidences a 75% conversion to organo-magnesium.
  • Example 5 Preparation of 2-(2-(l-methyl-l-phenyl-ethyl)-2H- tetrazol-5-yl)-phenyl)-magnesium isopropylamide (V)
  • a 2 liters reactor is loaded with 600 ml of a magnesium diisopropylamide 0.75 M solution and 100 g of 2-(l -methyl- 1-phenyl-ethyl)- 5-phenyl-2H-tetrazole.
  • the mixture is refluxed for 4 hrs., then the reaction is seeded with 1 g of 2-(2-(l -methyl- 1-phenyl-ethy l)-2H-tetrazol-5-yl)-phenyl)- magnesium isopropylamide and then refluxed for a further 16 hrs.
  • the resulting mixture is cooled to 20-30°C, filtered by suction under inert atmosphere, then washed with THF to afford 102 g 2-(2-(l -methyl- 1-phenyl- ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide.
  • Example 6 Preparation of 2-(2-(l-methyl-l-phenyl-ethyl)-2H- tetrazol-5-yl)-phenyl)-boronic acid (II)
  • a 2 liters reactor is loaded with 102 g 2-(2-(l -methyl- 1-phenyl-ethyl)- 2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide and 250 ml of THF.
  • the suspension is cooled to 0-5°C and added with 58.3 g of trimethylborate in 20 minutes.
  • the mixture is then gradually heated to room temperature, left under stirring for at least 2 hrs., then diluted to pH 2.5-3 with phosphoric acid.
  • the resulting solution is heated to 30-35°C and kept at this temperature for 2 hrs., then stirring is interrupted and the aqueous phase is discarded. 250 ml of water are added to the organic phase and the resulting mixture is concentrated under vacuum to remove THF. The resulting mixture is diluted with 60 ml of toluene and left under stirring at room temperature for at least 3 hrs. The precipitated product is filtered and washed with water and toluene. After drying a 60°C under vacuum, 60 g of 2-(2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl)- phenyl)-boronic acid are obtained.
  • Example 7 Preparation 2-(2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol- 5-yl)-phenyl)-boronic acid methyl ester (II)
  • a 2 liters reactor is loaded with 102 g 2-(2-(l -methyl- 1 -phenyl -ethyl) - 2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide and 250 ml of THF.
  • the suspension is cooled to 0-5°C and added with 58.3 g of trimethylborate, in 20 minutes.
  • the mixture is then gradually heated to room temperature, left under stirring for at least 2 hrs., then diluted with water and toluene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

A process for the preparation of phenyltetrazole derivatives of formula (II) wherein R and Y are as defined in the disclosure, by direct ortho-metallation of (tetrazol-5-Ϝl)benzene. The compounds of formula (II) are useful intermediates for the preparation of angiotensin II antagonists.

Description

A PROCESS FOR THE PREPARATION OF PHENYLTETRAZOLE DERIVATIVES
FIELD OF THE INVENTION The present invention relates to a process for the preparation of substituted phenyltetrazole compounds, useful as intermediates for the preparation of angiotensin II antagonists. BACKGROUND OF THE INVENTION Angiotensin II antagonists are used, for example, in the treatment of hypertension, anxiety, glaucoma and heart failure. A number of these compounds are characterized by a biphenyltetrazole moiety and can be represented by the following formula (I)
Figure imgf000002_0001
(I) wherein Z is an optionally substituted heterocycle containing at least one nitrogen atom; or an amido residue. Preferably, the residue Z has the following meanings, which identify specific angiotensin II antagonists: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl (losartan); 2-ethoxy-7-carboxy- 1 H-benzimidazol- 1 -yl (candesartan); 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl (irbesartan); and (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoylamino (valsartan). Key intermediates for the preparation of compounds of formula (I) are 2-substituted phenyltetrazoles of formula (II)
Figure imgf000003_0001
in which R is hydrogen, a protecting group or a salifying group and Y is a -B(OR )2 group, wherein each R4 is independently hydrogen or Cι-C6 alkyl; or a ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine. A number of processes for the preparation of the compounds of formula (II) are known. For example, the process disclosed in US 5,039,814 or in WO 93/10106 comprises the ortho-litiation of the phenyltetrazole and the subsequent transmetallation reaction. The main drawbacks of said process resides in the need to use an organo-lithium compound, i.e. a compound which requires specific safety precautions when used on an industrial scale, due to its high flammability and reactivity. WO 99/01459 partly solves the problems deriving from the use of organo-lithium compounds by reacting a compound of formula (III)
Figure imgf000003_0002
(in) in which R is as defined above, with a Grignard reagent of formula R MgX in which R! is C C6 alkyl or benzyl and X is as defined above; in the presence of catalytic amounts of a secondary amine, which acts as a disaggregant of the Grignard reagent; thereby obtaining a compound of formula (IV)
Figure imgf000004_0001
(IV) wherein R and X are as defined above. This compound is however hardly reactive and cannot be used as such in "cross-coupling" reactions for the preparation of compounds of formula (I). Therefore, this compound is subjected to a transmetallation reaction, according to known procedures, to obtain a compound of formula (II) as defined above, which is much more reactive. The use of a Grignard reagent, compared with an organo-lithium compound, is undoubtedly safer, but still potentially dangerous on an industrial scale and still requires specific procedures. It is therefore evident that there is still need for an alternative process for the preparation of compounds of formula (II), in particular a process which does not require the use of Grignard reagents. DETAILED DESCRIPTION OF THE INVENTION It has now been found a process for the preparation of compounds of formula (II) which does not involve the use of Grignard reagents and is therefore safer; furthermore, this process is more advantageous from the industrial point of view as it provides higher yields, is less costly and involves less preparation steps. Therefore, the present invention relates to a process for the preparation of compounds of formula (II)
Figure imgf000005_0001
wherein R is hydrogen, a protecting group or a salifying group and Y is a -B(OR4)2 group, in which each R4 is independently hydrogen or Ci-Cβ alkyl; or a -ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine; which comprises the reaction of a compound of formula (V)
Figure imgf000005_0002
(V) wherein R is as defined above and R2 and R3, which can be the same or different, are straight or branched Cι-C6 alkyl, C -C6 cycloalkyl, trialkylsilyl, or R2 and R3, taken together with the nitrogen atom they are linked to, form a saturated, optionally substituted, heterocyclic ring, containing one to two further heteroatoms independently selected from nitrogen, oxygen and sulfur; either with a compound of formula (VI) ZnX2 (VI) wherein X is as defined above; or with a compound of formula (Via) B(OR'4)3 (Via) wherein each R'4 is independently C C6 alkyl, and, if desired, the subsequent hydrolysis of the resulting boronic ester of formula (II). The term "protecting group R" means a tetrazole ring protecting group known in the art, preferably a straight or branched Ci-Cβ alkyl, optionally substituted with one or more phenyl groups, in their turn optionally substituted, for example with C1-C4 alkoxy or C C alkylthio. Preferred examples of R are tert-butyl, para-methoxybenzyl, trityl and 1 -methyl- 1- phenylethyl, the latter being particularly preferred. The term "salifying group R" means, for example, an alkali or alkaline- earth metal, preferably sodium, potassium or magnesium, more preferably sodium. When R2 and R3 are Cι-C6 alkyl groups, they are preferably C3-C6 alkyl groups, more preferably isopropyl, sec-butyl, tert-butyl, most preferably isopropyl. When R2 and R3 are C3-C6 cycloalkyl groups, they are preferably cyclopentyl and cyclohexyl. When R2 and R3 are trialkylsilyl groups, they are preferably trimethylsilyl. When R is a CpCg alkyl group, it is preferably a straight or branched C1-C4 alkyl group, more preferably methyl, ethyl propyl, isopropyl, sec-butyl, tert-butyl, most preferably methyl, ethyl or isopropyl. The term "heterocyclic ring" as defined above preferably means piperidine, piperazine, morpholine, pyrrolidine, more preferably 2,2,6,6- tetramethy lpiperidine . The reaction of a compound of formula (V) with a compound of formula (VI) or (Via) is typically carried out in an ether solvent, preferably ethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof, or mixtures thereof with apolar solvents, preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran. The stoichiometric ratio of a compound of formula (VI) or (Via) to a compound of formula (V) ranges from approx. 1.0 to approx. 5.0, preferably from 1.1 to 3.0. The reaction is carried out at a temperature ranging from about 20°C to the reflux temperature of the reaction mixture. Reaction times depend on the temperature and the progress of the reaction is monitored by conventional analytical methods. The hydrolysis of a boronic ester of formula (II) to obtain a corresponding compound of formula (II) in which R is hydrogen, can be carried out according to known methods, for example by addition of a mineral or organic acid, in particular phosphoric, hydrochloric or acetic acid, to the reaction mixture. The compounds of formula (II) wherein R is a 1 -methyl- 1-phenyl-ethyl group and Y is a -B(OR4)2 group, in which R4 is as defined above, are novel and are a further object of the invention. Preferred examples are those in which each R4 is independently hydrogen, methyl, ethyl or isopropyl. Particularly preferred are the following compounds: • 2-[2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid; • 2-[2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid methyl ester; and • 2-[2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid isopropyl ester. The compounds of formula (V) are novel and are a further object of the present invention. Preferred examples of compounds of formula (V) are: • 2-[2-t-butyl-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; • 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; and • 2- [2-(l -methyl- 1 -phenyl-ethyl)-2H-tetrazol- 5 -yl] -phenyl magnesium diisopropylamide, in particular the latter. Compounds (V) can be prepared by reaction of compounds of formula
(III)
Figure imgf000008_0001
(πi) wherein R is as defined above, with compounds of formula (VII) Mg(NR2R3)2 (VII) wherein R2 and R3 are as defined above. The reaction between a compound of formula (III) and a compound of formula (VII) is typically carried out in an ether solvent, for example ethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof, or mixtures thereof with apolar solvents, preferably hexane, heptane, cyclohexane, benzene, toluene and xylene, more preferably tetrahydrofuran. The stoichiometric ratio of a compound of formula (VII) to a compound of formula (III) ranges from approx. 0.5 to approx. 3.0, preferably from 1.0 to 2.0. The reaction is carried out at a temperature ranging from about 20°C to the reflux temperature of the reaction mixture, preferably at the reflux temperature. Reaction times depend on the temperature, and the progress of the reaction is monitored by conventional analytical methods. The resulting compound of formula (V), which can optionally be isolated, is then reacted with a compound of formula (VI) or (Via). The compounds of formula (VII) can be obtained according to known processes, for example as described in DE 100 61 317. Preferably, the resulting compounds of formula (VII) are reacted with compounds of formula (III) without being isolated. A further object of the invention is the use of a compound of formula (V) for the preparation of a compound of formula (I)
Figure imgf000009_0001
D or a pharmaceutically acceptable salt thereof, in which Z is an optionally substituted heterocycle, containing at least one nitrogen atom; or an amido residue. Preferably, a compound of formula (V) is used for the preparation of a compound of formula (I) in which Z is selected from: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl; 2-ethoxy-7-carboxy- 1 H-benzimidazol- 1 -yl; 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl and (S)-N-( 1 -carboxy-2-methy lprop- 1 -yl)-N-pentanoylamino, most preferably 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl. The preparation of a compound of formula (I) from a compound of formula (II) can be carried out for example according to EP 846117 or WO 95/32962. The following examples further illustrate the invention. Example 1: Preparation of 2-[2-(l-methyI-l-phenyl-ethyl)-2H- tetrazol-5-yl] -phenyl zinc chloride (II) A mixture of 2-(l -methyl- 1-phenyl-ethyl)- 5 -phenyl-2H-tetrazole (5.0 g;
20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. The mixture is subsequently cooled and diluted with a zinc chloride solution (5.4 g; 40.0 mmoles) in THF (29 ml). The resulting mixture is refluxed for a further 2 hrs. ^-NMR analysis, after treatment with deuterated water, evidences a conversion to organo-zinc higher than 96%. Example 2: Preparation of 2- [2-Trityl-2H-tetrazol-5-yl] -phenyl magnesium diisopropylamide (V) A mixture of l-trityl-5-phenyl-2H-tetrazole (7.9 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. ^-NMR analysis, after treatment with deuterated water, evidences a
67% conversion to organo-magnesium. Example 3: Preparation of 2- [2-t-butyl-2H-tetrazol-5-yl] -phenyl magnesium diisopropylamide (V) A mixture of l-t-butyl-5-phenyl-2H-tetrazole (4.1 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. ^-NMR analysis, after treatment with deuterated water, evidences a 75% conversion to organo-magnesium. Example 4: Preparation of 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide (V) A mixture of 5-phenyl-2H-tetrazole sodium salt (3.4 g; 20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxed for 3 hrs. -NMR analysis, after treatment with deuterated water, evidences a 75% conversion to organo-magnesium. Example 5: Preparation of 2-(2-(l-methyl-l-phenyl-ethyl)-2H- tetrazol-5-yl)-phenyl)-magnesium isopropylamide (V) A 2 liters reactor is loaded with 600 ml of a magnesium diisopropylamide 0.75 M solution and 100 g of 2-(l -methyl- 1-phenyl-ethyl)- 5-phenyl-2H-tetrazole. The mixture is refluxed for 4 hrs., then the reaction is seeded with 1 g of 2-(2-(l -methyl- 1-phenyl-ethy l)-2H-tetrazol-5-yl)-phenyl)- magnesium isopropylamide and then refluxed for a further 16 hrs. The resulting mixture is cooled to 20-30°C, filtered by suction under inert atmosphere, then washed with THF to afford 102 g 2-(2-(l -methyl- 1-phenyl- ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide. XH NMR (CD3OD), (δ, ppm): 8.15 (1H, m); 7.43 (3H, m); 7.31 (3H, m); 7.18 (2H, d); 2.91 (2H, set); 2.20 (6H, s); 1.02 (12H, d). Example 6: Preparation of 2-(2-(l-methyl-l-phenyl-ethyl)-2H- tetrazol-5-yl)-phenyl)-boronic acid (II) A 2 liters reactor is loaded with 102 g 2-(2-(l -methyl- 1-phenyl-ethyl)- 2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide and 250 ml of THF. The suspension is cooled to 0-5°C and added with 58.3 g of trimethylborate in 20 minutes. The mixture is then gradually heated to room temperature, left under stirring for at least 2 hrs., then diluted to pH 2.5-3 with phosphoric acid. The resulting solution is heated to 30-35°C and kept at this temperature for 2 hrs., then stirring is interrupted and the aqueous phase is discarded. 250 ml of water are added to the organic phase and the resulting mixture is concentrated under vacuum to remove THF. The resulting mixture is diluted with 60 ml of toluene and left under stirring at room temperature for at least 3 hrs. The precipitated product is filtered and washed with water and toluene. After drying a 60°C under vacuum, 60 g of 2-(2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl)- phenyl)-boronic acid are obtained. 1H NMR (DMSO d6), (δ, ppm): 8.00 (2H, s); 7.90 (1H, m); 7.48 (3H, m); 7.31 (3H, m); 7.18 (2H, d); 2.15 (6H, s). Example 7: Preparation 2-(2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol- 5-yl)-phenyl)-boronic acid methyl ester (II) A 2 liters reactor is loaded with 102 g 2-(2-(l -methyl- 1 -phenyl -ethyl) - 2H-tetrazol-5-yl)-phenyl)-magnesium isopropylamide and 250 ml of THF. The suspension is cooled to 0-5°C and added with 58.3 g of trimethylborate, in 20 minutes. The mixture is then gradually heated to room temperature, left under stirring for at least 2 hrs., then diluted with water and toluene. The aqueous phase is discarded and the organic phase is evaporated to a residue. 70 g of an oil consisting of 2-(2-(l -methyl- l-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)- boronic acid methyl ester methyl ester. 1H NMR (DMSO d6), (δ, ppm): 7.90 (1H, m); 7.48 (3H, m); 7.31 (3H, m); 7.18 (2H, d); 3.17 (6H, s); 2.15 (6H, s). Following the same procedure, 2-(2-(l -methyl- 1-phenyl-ethy 1)-2H- tetrazol-5-yl)-phenyl)-boronic acid isopropyl ester is obtained.

Claims

CLAIMS A process for the preparation of a compound of formula (II)
Figure imgf000013_0001
in which R is hydrogen, a protecting group or a salifying group and Y is a -B(OR4)2 group, wherein each R4 is independently hydrogen or C C6 alkyl; or a -ZnX group, wherein X is a halogen atom selected from chlorine, bromine and iodine; which comprises the reaction of a compound of formula (V)
Figure imgf000013_0002
(V) wherein R is as defined above and R2 and R3, which can be the same or different, are straight or branched -Cό alkyl, C3-C6 cycloalkyl, trialkylsilyl, or R2 and R3, taken together with the nitrogen atom they are linked to, form a saturated, optionally substituted, heterocyclic ring, containing one to two further heteroatoms independently selected from nitrogen, oxygen and sulfur; either with a compound of formula (VI) ZnX2 (VI) wherein X is as defined above; or with a compound of formula (Via) B(OR'4)3 (Via) wherein each R'4 is independently Cι-C6 alkyl, and, if desired, the subsequent hydrolysis of the resulting boranic ester of formula (II).
2. A process as claimed in claim 1, in which the stoichiometric ratio of a compound of formula (VI) or (Via) to a compound of formula (V) ranges from 1.0 to 5.0.
3. A process as claimed in claim 2, in which the stoichiometric ratio of a compound of formula (VI) or (Via) to a compound of formula (V) ranges from 1.1 to 3.0.
4. A process as claimed in claim 1 or 2, in which the reaction is carried out in an ether solvent or mixtures thereof with an apolar solvent, at a temperature ranging from 20°C to the reflux temperature.
5. A process as claimed in claim 1, in which a compound of formula (V) is prepared by reaction between a compound of formula (III)
Figure imgf000014_0001
(III) wherein R is as defined in claim 1 , with a compound of formula (VII) Mg(NR2R3)2 (VII) wherein R2 and R3 are as defined in claim 1.
6. A process as claimed in claim 5, in which the stoichiometric ratio of a compound of formula (VII) to a compound of formula (III) ranges from 0.5 to 3.0.
7. A process as claimed in claim 6, in which the stoichiometric ratio of a compound of formula (VII) to a compound of formula (III) ranges from 1.0 to 2.0.
8. A compound of formula (II), as defined in claim 1, wherein R is a 1- methyl- 1-phenyl-ethyl group and Y is a -B(OR4)2 group, in which R4 is as defined in claim 1.
9. A compound as defined in claim 8, wherein each R4 is independently hydrogen, methyl, ethyl or isopropyl.
10. A compound as defined in claim 8, which is: • 2-[2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid; • 2-[2-(l-methyl-l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid methyl ester; or • 2-[2-( 1 -methyl- l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid isopropyl ester.
11. A compound of formula (V)
Figure imgf000015_0001
(V) wherein R, R2 and R3 are as defined in claim 1.
12. A compound as defined in claim 11, which is: • 2-[2-t-butyl-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; • 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide; or • 2-[2-(l -methyl- l-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide.
13. The use of a compound of formula (V), as defined in claim 11 or 12, for the preparation of a compound of formula (I)
Figure imgf000016_0001
(I) in which Z is an optionally substituted heterocycle containing at least one nitrogen atom; or an amido residue; or of a pharmaceutically acceptable salt thereof.
14. The use as claimed in claim 13, wherein in the compound of formula (I) the residue Z is selected from: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-l-yl; 2-ethoxy-7-carboxy- 1 H-benzimidazol- 1 -yl; 2-butyl-l,3-diaza-spiro[4,4]non-l-en-4-on-3-yl and (S)-N-( 1 -carboxy-2-methylprop- 1 -yl)-N-pentanoylamino.
PCT/EP2004/008576 2003-08-08 2004-07-30 A process for the preparation of phenyltetrazole derivatives WO2005014560A1 (en)

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CA002534892A CA2534892A1 (en) 2003-08-08 2004-07-30 A process for the preparation of phenyltetrazole derivatives
DE602004010530T DE602004010530T2 (en) 2003-08-08 2004-07-30 PROCESS FOR THE PREPARATION OF PHENYLTETRAZOL DERIVATIVES
DK04763657T DK1660463T3 (en) 2003-08-08 2004-07-30 Process for the preparation of phenyltetrazole derivatives
JP2006522299A JP2007501770A (en) 2003-08-08 2004-07-30 Method for producing phenyltetrazole derivative
EP04763657A EP1660463B1 (en) 2003-08-08 2004-07-30 A process for the preparation of phenyltetrazole derivatives
PL04763657T PL1660463T3 (en) 2003-08-08 2004-07-30 A process for the preparation of phenyltetrazole derivatives
MXPA06001485A MXPA06001485A (en) 2003-08-08 2004-07-30 A process for the preparation of phenyltetrazole derivatives.
NO20060603A NO331810B1 (en) 2003-08-08 2006-02-07 Process for the preparation of phenyltetrazole derivatives
IL173582A IL173582A0 (en) 2003-08-08 2006-02-07 A process for the preparation of phenyltetrazole derivatives
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EP1905770A1 (en) 2006-09-27 2008-04-02 Dipharma Francis S.r.l. A process for the preparation of phenyltetrazole compounds
ES2300175A1 (en) * 2006-02-14 2008-06-01 Inke, S.A. Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond
JP2009500434A (en) * 2005-07-11 2009-01-08 ノバルティス アクチエンゲゼルシャフト Metal salt of 2 '-(1H-tetrazol-5-yl) -1.1'-biphenyl-4-carboxaldehyde

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ES2264641A1 (en) * 2005-06-17 2007-01-01 Quimica Sintetica, S.A. Method for obtaining benzimidazole derivatives and intermediates thereof
JP2009500434A (en) * 2005-07-11 2009-01-08 ノバルティス アクチエンゲゼルシャフト Metal salt of 2 '-(1H-tetrazol-5-yl) -1.1'-biphenyl-4-carboxaldehyde
ES2300175A1 (en) * 2006-02-14 2008-06-01 Inke, S.A. Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond
EP1905770A1 (en) 2006-09-27 2008-04-02 Dipharma Francis S.r.l. A process for the preparation of phenyltetrazole compounds

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