EP1891025A1

EP1891025A1 - Method for the production of substituted azoles

Info

Publication number: EP1891025A1
Application number: EP06743081A
Authority: EP
Inventors: Rainer Bruns; Hermann Uhr; Erasmus Vogl
Original assignee: Lanxess Deutschland GmbH
Current assignee: Lanxess Deutschland GmbH
Priority date: 2005-06-07
Filing date: 2006-05-27
Publication date: 2008-02-27
Also published as: JP2008542408A; DE102005025992A1; US20090306397A1; WO2006131228A1; KR20080019609A; CN101193873A

Abstract

Disclosed is a method for producing substituted azoles. Said method makes it possible to produce compounds of general formula (I) and/or the salts thereof and/or the acid addition compounds thereof, wherein the substituents R1 and R2, A, and B have the meaning indicated in the description, at a good yield as well as in a simple, economically favorable manner.

Description

Process for the preparation of substituted azoles

The present invention relates to a novel process for the preparation of substituted azoles, in particular substituted 1H-tetrazoles and substituted 1H-triazoles.

Azoles, in particular the 5-substituted 1H-triazoles and -tetrazoles, are used inter alia as pharmaceutically active substances in medicine or are used, for example, in the protection of plants and technical materials as biocides.

For the synthesis of 5-substituted 1H-triazoles and -tetrazoles, one usually starts from the corresponding 5-H-substituted compounds. These are usually converted to the corresponding 5-substituted derivatives by lithiation at very low temperature and treatment with an electrophile. The following example serves to explain the closest prior art.

Thus, Yoshitaka Satoh and Nicholas Marcopulos describe a method [Tetrahedron Letters (1995), 36 (11), 1759-62] for applying the lithiation of 1-benzyl and 1-p-methoxybenzyl tetrazoles at the 5-position. Reaction with n-butyllithium followed by treatment with electrophiles gave 5-functionalized 1-benzylic tetrazoles. A disadvantage of the method, however, are the extremely low temperature (-98 ⁰ C) and the use of n-BuLi.

In summary, lithiation, as the closest prior art, is the method of choice for derivatization of the 5-position, for example by halogens, the low temperature, the use of air-sensitive and less-expensive metallating reagents such as n-BuLi and especially the complete instability of the metallated intermediate at temperatures above -78 ° C are very disadvantageous.

The object of the present invention was thus to provide an improved process for the preparation of substituted azoles.

Surprisingly, a new process for the preparation of substituted azoles has now been found, whereby the lithiation described in the prior art and the implementation of the reaction at low temperature can be avoided.

The present invention relates to a process for the preparation of substituted azoles of the general formula (I), and / or their salts and / or their acid addition compounds,

wherein

A is N, CH or CR ³ ,

B is N, CH or CR ⁴ ,

with the proviso that at least one of A and B is N,

R ^{1 is} hydrogen or in each case optionally substituted alkyl, alkenyl, alkynyl or phenyl,

R ^{2 is} F, Cl, Br, I, OH, SH, CN, SCN, or in each case optionally substituted alkyl, cycloalkyl, phenethyl, benzyl, acyl, thioacyl, hydroxymethylene, or methylene thiol,

Each R ³ is optionally substituted alkyl, alkenyl, alkynyl, phenyl or phenethyl, and

R ^{4 is} in each case optionally substituted alkyl, alkenyl, alkynyl, phenyl or phenethyl,

by reacting compounds of the formula (II), and / or salts thereof and / or their acid addition compounds,

wherein

A, B and R ^{1 have} the meaning given for formula (I),

with at least one electrophile, at a temperature between ^{0 0} C and 100 ⁰ C, in the presence of at least one base, optionally in the presence of a phase transfer catalyst and optionally in the presence of a solvent or solvent mixture. The process according to the invention preferably serves for the preparation of compounds of the general formula (I) in which

R ^{1 is} hydrogen or straight-chain or branched C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen; nitro; cyano; hydroxy; C _r C ₆ alkoxy which is optionally substituted from 1 to 9 times, identically or differently, by halogen; C 1 -C ₆ -alkylthio which is optionally substituted by 1 to 9 times, the same or different by halogen; amino; Monoalkylamino having straight-chain or branched QC ₆ -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C ₁ -C ₆ -alkyl radicals; Phenyl which is optionally monosubstituted to polysubstituted by the same or different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, (alkoxy) carbonyl, carboxyl, amino, monoalkylamino or dialkylamino,

or

R ^{1 is} phenyl which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino,

R ^{2 is} F, Cl, Br, I, OH, SH, CN, SCN, straight-chain or branched C 1 -C ₈ -alkyl or Q-cyclo-cycloalkyl,

or

is phenethyl or benzyl, which is in each case optionally mono- to polysubstituted by identical or different substituents by halogen; nitro; cyano; hydroxy; C _r C ₆ alkoxy which is optionally substituted from 1 to 9 times, identically or differently, by halogen; C ₁ -C ₆ -alkylthio which is optionally 1 to 9 times, identical or different

Halogen is substituted; amino; Monoalkylamino having straight-chain or branched C ₁ -C ₆ -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C ₁ -C ₆ -alkyl radicals; Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino,

Monoalkylamino or dialkylamino is substituted,

or is acyl or thioacyl, each of which is optionally substituted by hydroxy; thiohydroxy; straight or branched C _r -C ₈ -alkyl which is optionally substituted 1-fold 9-bis, or equal to different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, Monoalkylamino, dialkylamino substituted; Q-

C 1 -C 10 cycloalkyl which is optionally substituted by 1 to 9 times, same or different by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy,

Alkylthio, haloalkylthio, acyl, acyloxy, (alkoxy) carbonyl, carboxyl, amino, monoalkylamino or dialkylamino,

or

is hydroxymethylene or methylenethiol, each of which is optionally substituted by straight-chain or branched C _r -C ₈ -alkyl which is optionally substituted 1-fold to 9 identical or different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy,

Haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, (alkoxy) -carbonyl,

Substituted carboxyl, amino, monoalkylamino, dialkylamino; C 1 -C 8 -cycloalkyl which is optionally 1 to 9 times, identical or different, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl,

Acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; Phenyl, which optionally one to several times, the same or different

Halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,

Haloalkylthio, acyl, acyloxy, (alkoxy) carbonyl, carboxyl, amino, monoalkylamino or dialkylamino,

A is N, CH or CR3,

in which

R 3 is straight-chain or branched C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy , Alkylthio, alkoxy, amino, and

B is N, CH or CR4,

in which R 4 represents straight-chain or branched CpCg-alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, which is in each case optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkylthio, Alkoxy, amino,

with the proviso that at least one of A and B stands for N.

The process according to the invention particularly preferably serves for the preparation of compounds of the general formula (I) in which

C _r C ₈ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl R ¹ represents hydrogen or straight-chain or branched, which to tetrasubstituted by identical or different substituents in each case optionally monosubstituted by fluorine; Chlorine; Bromine; nitro; cyano; hydroxy; Ci-C ₄ alkoxy which optionally 1 to 5-fold, same or different by fluorine, chlorine or

Bromine is substituted; C 1 -C ₄ -alkylthio which is optionally substituted by 1 to 5 times, the same or different, by fluorine, chlorine or bromine; amino; Monoalkylamino having straight-chain or branched C 1 -C 4 -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C 1 -C ₄ -alkyl radicals; Phenyl, which optionally one to four times, identically or differently by fluorine, chlorine. Bromine. nitro,

Cyano, hydroxy, C ₁ -C ₄ -alkyl. Q-Gi-haloalkyl which 1- to 5-fold identical or substituted by fluorine, chlorine or bromine, Ci-C ₄ alkoxy, C ₁ -C ₄ - halogenoalkoxy which is 1- to 5-fold identical or different substituents by fluorine, chlorine or bromine, C ₁ -C ₄ -AlkVItMo, G-Cd-haloalkylthio which is monosubstituted or disubstituted by one to five times by fluorine, chlorine or bromine, C ₁ -Cn-AcVl. C ₁ -Gr

Acyloxy, Q-Cfi-alkoxycarbonyl, carboxyl. Amino, monoalkylamino having straight-chain or branched C 1 -C ₄ -alkyl radicals, or dialkylamino being substituted by identical or different, straight-chain or branched C 1 -C ₄ -alkyl radicals,

or

R ^{1 is} phenyl which is optionally substituted one to four times, identically or differently by fluorine; Chlorine; Bromine; nitro; cyano; hydroxy; C _r C ₄ alkyl; C 1 -C ₄ -haloalkyl which is monosubstituted or disubstituted by fluorine, chlorine or bromine; C 1 -C ₄ -alkoxy; C] -C ₄ -haloalkoxy which is monosubstituted or disubstituted by fluorine, chlorine or bromine; C 1 -C ₄ -alkylthio; QC ₄ - Halogenalkylthio which is 1 to 5 times the same or different by fluorine, chlorine or

Bromine is substituted; Ci-C ₄ acyl; QQ acyloxy; C 1 -C ₄ alkoxycarbonyl; carboxyl; amino; Monoalkylamino having straight-chain or branched C 1 -C ₄ -alkyl radicals, or Dialkylamino having the same or different, straight-chain or branched C ₁ -C ₄ -alkyl radicals,

_r F, Cl, Br, I, OH, SH, CN, SCN, straight-chain or verzweigetes C Ci ₀ alkyl or C _r Cio-cycloalkyl,

or

is benzyl, which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino,

or

is acyl or thioacyl, which is optionally substituted by

hydroxy; thiohydroxy; straight-chain or branched Q-Cg-alkyl which is optionally 1 to 9-fold, identical or different, by halogeno, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino , Dialkylamino is substituted; Q-Cio-cycloalkyl which optionally 1 to 9-fold, the same or different

Halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; or phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl,

Carboxyl, amino, monoalkylamino or dialkylamino,

or

represents hydroxymethylene or methylene thiol which is in each case optionally substituted by straight-chain or quenched Q-Cg-alkyl which is optionally 1 to 9-fold, identical or different, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy,

Haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; C 1 -C ₁₀ -cycloalkyl which is optionally 1 to 9 times, identical or different, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino ,. Dialkylamino is substituted; or

Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, Haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino or dialkylamino,

A is N, CH or CR3,

in which

R ^{3 represents} straight-chain or branched C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy , Alkylthio, alkoxy, amino

and

B is N, CH or CR4,

in which

R4 represents straight-chain or branched Q-Cg-alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl which is in each case optionally mono- to polysubstituted identically or differently by halogen, nitro, cyano, hydroxyl, Alkylthio, alkoxy, amino,

with the proviso that at least one of A and B stands for N.

Very particular preference is given to the erfmdungsgemäße process for the preparation of compounds of formula (I), in which

R ^{1 is} hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, Allyl, vinyl, propargyl, wherein said alkyl radicals are each optionally substituted one to four times, identically or differently by fluorine, chlorine, bromine, nitro, cyano, hydroxy, methoxy, ethoxy, n-

Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, trifluoromethylthio, amino, methylamino, ethylamino, n-propylamino, iso Propylamino, dimethylamino, diethylamino, methylethylamino, di-n-propylamino di-iso-propylamino or by phenyl which optionally substituted one to three times by fluorine, chlorine, bromine,

Nitro, cyano, hydroxy, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, tert -butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, iso -propoxy, n Butoxy, iso-butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, methylthio, ethylthio, n-propylthio, iso-propylthio, trifluoromethylthio, formyl, acetyl, acetyloxy, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, methylamino, ethylamino, n -Propylamino, iso-propyl amino, dimethylamino, diethylamino, methylethylamino, di-n-propylamino or diisopropylamino,

or

R ^{1 is} phenyl which is optionally monosubstituted to trisubstituted by fluorine, chlorine, bromine, nitro, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl , tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, Trifluoromethylthio, formyl, acetyl, acetyloxy, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, methylamines, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, di-n-propylamino di-iso-propylamino,

R ^{2 is} F, Cl, Br, I, OH, SH, CN, SCN,

or

is benzyl, hydroxymethylene or methylene thiol which is optionally substituted by straight-chain or branched Ci-Ci ₀ - alkyl which optionally

1 to 9-fold, identical or different, by halogen, nitro, cyano, alkyl, haloalkyl,

Alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl,

Substituted carboxyl, amino, monoalkylamino, dialkylamino; Ci-Ci _0-cycloalkyl which is optionally substituted 1-fold to 9 identical or different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl,

Acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; or phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy,

A is N or CH,

and

B is N or CH,

with the proviso that at least one of A and B stands for N. The inventive method is also used for the preparation of salts and / or acid addition compounds of the compounds of formula (I), such as their hydrohalides, hydrophosphonates or hydrosulfates, for example, the corresponding salts and / or acid addition compounds of the formula (II) can be used.

To carry out the process according to the invention, compounds of the formula (II) are used. The substituents R 1, A and B in formula (H) correspond in their general, preferred, particularly preferred and very particularly preferred meaning to the corresponding meanings of the substituents R 1, A and B in formula (I) listed above.

Suitable electrophiles for carrying out the process according to the invention are, for example, halogens such as fluorine, chlorine, bromine, iodine, aldehydes, e.g. benzaldehyde,

Cyclohexane carbaldehyde, nitriles such as cyclohexane carbonitrile or amides such as Weinrebamid.

The electrophiles used are preferably chlorine, bromine, iodine and aldehydes or mixtures thereof. The electrophiles are generally used in amounts of 0.5 to 15 equivalents based on the azole (TT). Preference is given to using 1 to 5 equivalents and, in particular 1.1 to 3 equivalents of electrophile based on azole.

The inventive method is generally conducted at temperatures between 0 ⁰ C and 100 ⁰ C, preferably between 15 ⁰ C and 80 ⁰ C, and particularly Favor performed between 20 ⁰ C and 5O ⁰ C.

Suitable solvents are all conventional organic solvents in question, which can not be affected or decomposed by the strongly basic environment such as, for example

Petroleum ether, n-octane, n-pentane, n-hexane, cyclohexane, n-pentane, toluene, benzene, THF,

Diethyl ether, methyl-f-butyl ether, diglyme, methanol, ethanol, isopropanol, n-butanol, CH ₂ Cl ₂ ,

CHCl ₃ . Mixtures of two or more solvents can also be used. Depending on

Solvents result in single-phase or two-phase systems. Under certain circumstances, it is also possible to work completely without additional organic solvent, as a result of which the organic

Phase is formed by the substrate. Preference is given to toluene, n-hexane, cyclohexane,

Diethyl ether, methyl-f-butyl ether or THF used.

Suitable bases for carrying out the process according to the invention are, for example, alkali metal hydroxides, phosphates, alcoholates and carbonates, and mixtures thereof. Particularly suitable are from the series of alkali hydroxides NaOH and KOH and from the series of carbonates Cs ₂ CO ₃ , CaCO ₃ , MgCO ₃ . Very particular preference is given to using aqueous solutions of NaOH and / or KOH, preferably 20% to 60% strength aqueous NaOH solution, more preferably aqueous 30% to 55% strength NaOH solution. The base will be in excess used to the substrate, preferably 1 to 100 equivalents, particularly preferably 10 to 60 equivalents per equivalent of substrate.

Examples of suitable phase transfer catalysts are 15-crown-5, 18-crown-6, tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraoctylammonium bromide, tetraoctylammonium chloride, methyltridecylammonium chloride, methyl trioctylammonium chloride (Aliquat 336) and methyl tributylammonium chloride. Preference is given to methyltrioctylammonium chloride (Aliquat 336) and methyl tributylammonium chloride or mixtures thereof.

Examples of surface-active additives are molecular sieve, silica gel or alumina powder.

The phase transfer catalyst can be used in an amount of 0.01 to 5 mol% based on the substrate, preferably 0.3 to 3 mol%.

You can perform the reaction at different stirring speeds and ensure a good mixing of the reactants. A stirring speed of over 10,000 revolutions per minute, such as when using an Ultra-Turrax, may be advantageous, but is not necessary in all cases.

The reaction can also be advantageously carried out in an ultrasonic bath.

The solution or suspension of the educt with the basic solution is advantageously stirred for some time, then the electrophile (possibly dissolved in a suitable solvent) is metered in at a suitable rate and stirred for some time. The optimum conditions depend on the substrate and its reactivity and solubility and must be determined, but are usually in the range of several minutes or hours.

The procedure according to the invention has a number of advantages over previously used methods: it is possible to work in very inexpensive solvents. Depending on the substrate, the reaction does not require cooling or heating. Room temperature can be the most favorable temperature. The reaction is fast. The bases used are very inexpensive and readily available. The reagents used are readily available, such as bromine or iodine. The

Control and optimization of the reaction can be achieved by suitable dosage of the reactants and the choice of solvents. The reaction is easily transferable to a large scale. The product is produced in high yield and purity in some examples and does not require further purification. The following examples according to the invention may serve to illustrate:

Examples:

1. Synthesis of 1-benzyl-5-iodo-1H-tetrazole

0.50 g of 1-benzyl-1H-tetrazole are suspended in 10 ml of hexane, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 1.18 g of iodine dissolved in 10 ml of tetrahydrofuran is added dropwise within 15 minutes. After the reaction has ended, the mixture is transferred to a separating funnel and the aqueous phase is extracted with ethyl acetate, the collected organic phases are washed with water, combined with brine and dried with sodium sulfate. After removing the

Solvent gives a beige crystals. Purified over silica gel column (mobile phase:

Ethyl acetate / n-hexane 35/65), 0.60 g of pure product is obtained (melting point 122 ° C, yield 67%).

2. Synthesis of 1-benzyl-5-iodo-1H-tetrazole

10 g of 1-benzyl-1H-tetrazole are dissolved in 200 ml of THF, 200 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 23 g of iodine dissolved in tetrahydrofuran is added dropwise within 15 minutes. When the reaction has ended, the mixture is transferred to a separatory funnel and the aqueous phase is extracted with ethyl acetate, the collected organic phases are washed with water, combined with brine and dried with sodium sulfate. After removal of the solvent to give a beige crystals, 16.2 g of pure product (melting point 122 ⁰ C, yield 91%).

3. Synthesis of 1-benzyl-5-bromo-1H-tetrazole

1.00 g of 1-benzyl-1H-tetrazole are dissolved in 10 ml of toluene, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 2.37 g of bromine dissolved in 10 ml of toluene is added dropwise within 15 minutes. After completion of the reaction is transferred to a separating funnel and the aqueous

Washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After removal of the solvent and

Purification over silica gel column gives 1.09 g of pure product (melting point 54 ° C, yield 73%).

4. Synthesis of 1-n-octyl-5-iodo-1H-tetrazole

0.50 g of n-octyl-lH-tetrazole are dissolved in 10 ml of THF, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 1.04 g of iodine dissolved in 10 ml of tetrahydrofuran is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After cleaning becomes 0.19 g pure product which crystallized after standing some (melting point 40 ⁰ C, yield 22%).

5. Synthesis of 1 -n-octyl-5-iodo-1H-tetrazole

0.50 g of n-octyl-1H-tetrazole are dissolved in 10 ml of toluene, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 1.04 g of iodine suspended in 10 ml of toluene is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase was washed with ethyl acetate, the collected organic

Washed with water, brine and dried with sodium sulfate. To

Purification is obtained 0.17 g of pure product, which crystallizes after standing for some time (melting point 40 ^° C., yield 20%).

6. Synthesis of 1-n-octyl-5-iodo-1H-tetrazole

0.50 g of n-octyl-1H-tetrazole are dissolved in 10 ml of toluene, 10 ml of 50% strength sodium hydroxide solution and 0.02 ml of aliquat are added, and the mixture is stirred well. 1.04 g of iodine suspended in 10 ml of toluene is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After purification, 0.30 g of pure product is obtained, which crystallizes after standing for some time (melting point 40 ° C., yield 35%).

7. Synthesis of (1-benzyl-1H-tetrazol-5-yl) (phenyl) methanol

1.00 g of 1-benzyl-1H-tetrazole are dissolved in 10 ml of THF, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well for 1 hour. Dissolved 0.944 g of benzaldehyde in 10 ml of THF is added dropwise within 15 minutes. After completion of the reaction is transferred to a separatory funnel and the aqueous phase washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After removal of the solvent and purification over silica gel column 0.60 g of pure product is obtained (melting point 81 ° C, yield 36%).

S. Synthesis of (1-benzyl-1H-tetrazol-5-yl) (cyclohexyl) methanol

5.6 g of 1-benzyl-1H-tetrazole are dissolved in 10 ml of THF, 10 ml of 50% strength sodium hydroxide solution are added and the mixture is stirred well for 1 hour. 5.6 g of cyclohexanaldehyde dissolved in 10 ml of THF is added dropwise within 15 minutes. After 20 minutes of stirring and completion of the reaction is transferred to a separatory funnel and the aqueous phase was washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After removal of the solvent and purification over silica gel column, 3.0 g of colorless viscous oil are obtained (R _f 1.5056, yield 32%).

Claims

claims

1. Process for the preparation of substituted azoles of the general formula (I), and / or their salts and / or their acid addition compounds,

o in which

A is N, CH or CR ³ ,

B is N, CH or CR ⁴ ,

with the proviso that at least one of A and B is N,

by reacting compounds of the formula (E), and / or salts thereof and / or their acid addition compounds,

wherein

A, B and R ^{1 have} the meaning given above for formula (I), with at least one electrophile, at a temperature between 0 ⁰ C and 100 ⁰ C, in the presence of at least one base, optionally in the presence of a phase transfer catalyst or surface-active additive and optionally in the presence of a solvent or solvent mixture.

2. The method according to claim 1, characterized in that a compound from the series of halogens, aldehydes, nitriles, amides or mixtures thereof is used as the electrophile.

3. The method according to at least one of claims 1 and 2, characterized in that the electrophile is used in an amount of 0.5 to 15 equivalents based on the azole (II).

4. The method according to at least one of claims 1 to 3, characterized in that are used as the base alkali metal hydroxides, phosphates, alcoholates and carbonates and mixtures thereof in an amount of 1 to 100 equivalents per equivalent of compound (II).

5. The method according to at least one of claims 1 to 4, characterized in that the phase transfer catalyst is a compound from the series 15-crown-5, 18-crown-6, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraoctylammonium bromide, tetraoctylammonium chloride, methyltridecyl - ammonium chloride, methyl tri-octyl ammonium chloride (Aliquat 336), methyl tributylammonium chloride or a mixture thereof is used.

6. The method according to at least one of claims 1 to 5, characterized in that the phase transfer catalyst in an amount of 0.01 to 5 mol% based on the compound (II) is used.

7. The method according to at least one of claims 1 to 6, characterized in that toluene, n-hexane, cyclohexane, diethyl ether, methyl-f-butyl ether, THF or mixtures thereof are used as the solvent.