DE4030039A1 - Prodn. of fungicidal triazole deriv. - namely 2-chloro:cyclopropyl-1-chloro:phenyl-3-triazolyl-2-propanol, from 2-chloro:cyclopropyl-1-chloro:benzyl-oxirane - Google Patents

Abstract

Prodn. of 2-(1-chlorocyclopropyl) -1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl) -2-propanol (I) is effected by (a) reacting 2-(1-chlorocyclopropyl) -2-(2-chlorobenzyl) -oxirane (II) with N2H4.H2O and (b) reacting the resulting 1-(2-chlorophenyl)-2-(1-chlorocyclopropyl) -2-hydroxypropylhydrazine (III) with formamidine acetate (IV). Steps (a) and (b) are effected in an alcohol or ether solvent, opt. in the presence of a phase-transfer catalyst. Step (a) is effected at 20-90 deg. C. Step (b) is effected at 50-130 deg. C. USE/ADVANTAGE - (I) is a fungicide (see EP 297345). The process gives high yields, e.g. 64-70%.

Description

The present invention relates to a new method for the production of the well-known 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ols, which has fungicidal properties.

It has already become known that numerous 2- Hydroxy-2-cyclopropyl-1- (1,2,4-triazol-1-yl) ethane derivatives can be made by making the appropriate Oxiranes with 1,2,4-triazole in the presence of a base and in the presence of an inert diluent (see EP-OS 02 97 345). A disadvantage of this method is, however, that in addition to the targeted 1,2,4-triazol-1-yl derivatives also relatively large amounts of the unwanted Form 1,3,4-triazol-1-yl derivatives. The separation this disruptive by-product is complex, and the yields of the desired substances in which the triazole radical is asymmetrically substituted therefore relatively low.  

It is also known that certain substituted in the 1-position 1,2,4-triazoles by reacting hydrazine derivatives accessible with formamidine acetate (cf. "N-C-N Chemicals; Formamidine; Building block for heterocycles and intermediates ", company publication of the SKW Trostberg Aktiengesellschaft, 1989). The synthesis of fungicidally active 1,2,4-triazol-1-yl derivatives this method has not yet been described.

It has now been found that 2- (1-chloro-cyclopropyl) - 1- (2-chlorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol of the formula

obtained when 2- (1-chloro-cyclopropyl) -2- (2-chlorobenzyl) oxirane of the formula

with hydrazine hydrate in the presence of a diluent and optionally in the presence of a phase transfer catalyst implements and the resulting  [1- (2-chlorophenyl) -2- (1-chlorocyclopropyl) -2-hydroxy] propyl hydrazine of the formula

with formamidine acetate of the formula

in the presence of a diluent and, if appropriate in the presence of a phase transfer catalyst implements.

It is extremely surprising that 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4-tri azol-1-yl) propan-2-ol of the formula (I) according to the invention Manufacture process in significantly higher yield leaves as according to the previously known method. In particular could not be expected to education undesirable by-products when working according to the invention Proceedings are omitted.

The method according to the invention is characterized by a Set of advantages. This is how synthesis enables it of 2- (1-chloro-cyclopropyl) -2- (2-chlorophenyl) -3- (1,2,4- triazol-1-yl) propan-2-ol in very good yields.  

In addition, the isolation of the invention producible substance from the accrued during the implementation Reaction mixture no problems. In front multiple recrystallizations are not necessary, because disruptive by-products are not included are.

The course of the method according to the invention can be achieved by the following formula scheme can be illustrated:

This when performing the method according to the invention 2- (1-chloro-cyclo propyl) -2- (2-chlorobenzyl) oxirane of the formula (II) prepare by using 1-chloro-1-chloroacetyl-cyclopropane of the formula  

with a Grignard compound of the formula

in the presence of diethyl ether at room temperature and the resulting 1-chloro-2- (1-chloro-cyclopro pyl) -3- (2-chlorophenyl) propan-2-ol of the formula

in the presence of a base, such as potassium tert-butoxide, Sodium methylate or potassium carbonate, and in Presence of a diluent, such as Dimethylformamide, methanol or n-butanol, at temperatures between 20 ° C and 60 ° C (see EP-OS 02 97 345).

This when performing the method according to the invention Formamidine acetate required as a reaction component of the formula (IV) is known (cf. "N-C-N Chemicals; Formamidines: Building block for heterocycles and intermediates ", SKW Trostberg Aktiengesellschaft company lettering, 1989).  

As diluents come when performing the first stage of the method according to the invention preferably Alcohols and ethers in question. Named as an example be methanol, ethanol, n-propanol, isopropanol, n-butanol, Diethyl ether, dioxane and tetrahydrofuran.

As phase transfer catalysts come in the implementation the first stage of the method according to the invention all common reaction accelerators of this type in question. Tetraalkyl ammonium salts can preferably be used, Trialkyl-aralkyl-ammonium salts or Tetraalkyl phosphonium salts such as tetrabutyl ammonium bromide or chloride, methyl trioctylammonium bromide, Triethyl-benzyl-ammonium-bromide or -chloride and benzyl-dodecyl-dimethyl-ammonium chloride (Zephirol). The phase transfer catalysts are in the generally in substance, in aqueous or alcoholic Solution used.

The reaction temperatures can be carried out the first stage of the process according to the invention within of a certain range can be varied. In general one works at temperatures between 20 ° C and 90 ° C, preferably between 30 ° C and 80 ° C.

When performing the first stage of the invention The procedure is generally carried out at normal pressure. But it is also possible under increased pressure to work.  

When performing the first stage of the invention The process is based on 1 mol of 2- (1-chloro-cyc lopropyl) -2- (2-chlorobenzyl) oxirane of the formula (II) in generally between 1.1 and 4.0 moles, preferably between 1.6 and 3.0 moles of hydrazine hydrate and optionally between 0.001 and 0.015 moles of a phase transfer catalyst a. The processing takes place after usual methods. In general, one proceeds in such a way that optionally after adding one beforehand Water miscible organic solvent organic phase separated, washed with water and under reduced pressure.

As diluents come when performing the second stage of the method according to the invention in turn preferably alcohols and ethers. Especially preferred solvents are those that already exist in connection with the description of the first Stage of the method according to the invention mentioned by way of example were.

As phase transfer catalysts come in the implementation the second stage of the method according to the invention again all the usual reaction accelerators of this Guy in question. Those are preferably usable Phase transfer catalysts that are already related with the description of the first stage of the invention Procedures were called. Also be here the phase transfer catalysts generally in bulk, used in aqueous or alcoholic solution.  

The reaction temperatures can also be carried out the second stage of the method according to the invention can be varied within a wide range. in the generally one works at temperatures between 50 ° C. and 140 ° C, preferably between 60 and 130 ° C.

Even when performing the second stage of the invention The process is generally carried out under normal pressure. However, it is also possible to increase or work under reduced pressure.

When performing the second stage of the invention The procedure is based on 1 mol of [1- (2- Chlorophenyl) -2- (1-chloro-cyclopropyl) -2-hydroxy] propylhydrazine of the formula (III) generally between 2.0 and 4.0 moles, preferably between 2.1 and 3.5 moles Formamidine acetate of formula (IV) and optionally between 0.001 and 0.015 moles of a phase transfer catalyst a. The processing takes place according to usual Methods. In general, you do that After the reaction has ended, the reaction mixture is reduced Pressure restricts the remaining residue an organic solvent, the resulting Solution in succession with dilute, aqueous alkali lye and washes water and, if necessary, after previous Concentrate cools down. The product that crystallizes out can possibly by usual methods of contaminants still contained are freed.

In a special variant, the invention The procedure can also be carried out as a one-pot reaction.  

In this case the isolation of the [1- (2- Chlorophenyl) -2- (1-chloro-cyclopropyl) -2-hydrox /] - propylhydrazine of formula (III).

When carrying out the method according to the invention can be used as the starting substance instead of 2- (1-chloro cyclopropyl) -2- (2-chlorobenzyl) oxirane of the formula (II) also 1-chloro-2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) propan-2-ol of formula (III) or a mixture of these two substances are used.

The 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4- triazol-1-yl) propan-2-ol of the formula (I) and its use to combat fungi is known (cf. EP-OS 02 97 345).

The method according to the invention is carried out illustrated by the following examples.

example 1

In a mixture of 50 g (1 mol) hydrazine hydrate and 200 ml of n-butanol are at temperatures between 65 and 70 ° C with stirring 121.5 g (0.5 mol) of 2- (1-chloro-cyclopro pyl) -2- (2-chlorobenzyl) oxirane within 2 hours dropped in. After the addition has ended, another 2 Stirred at 65 to 70 ° C and then to 20 ° C cooled down. The aqueous phase is separated off and stirred remaining organic phase with 50 ml of water, separates the organic phase and constricts this organic phase at 70 ° C under reduced pressure.

The remaining residue is mixed with 200 ml of ethanol. The resulting solution is added at 70 to 75 ° C. with stirring, 114 g (1.1 mol) of formamidine acetate in portions added. When the addition is complete, the reaction mixture 10 hours while stirring at temperatures heated between 75 and 80 ° C. Then works one by moving the reaction mixture at 70 ° C concentrated under reduced pressure. You take the remaining one Residue at 70 ° C in 350 ml of methylcyclohexane and after adding 200 ml with 45 wt .-% aqueous Sodium hydroxide solution to a pH between 7.5 and 8.0  a. The aqueous phase is separated off and the organic Phase is twice with 200 ml of water at 70 ° C. washed. The organic phase is then separated off and slowly cooled to 20 ° C. The one that fails Solid is suctioned off, twice with 100 ml of methylcyclohexane washed and dried. You get on this way 117.5 g of a product that is 85% made up of 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4-triazol-1-yl) prop-an-2-ol consists. The yield is calculated afterwards to 64% of theory.

Preparation of the starting substance:

A solution of 225 g (1.40 mol) of 2-chloro-benzyl chloride in 500 ml of absolute diethyl ether at reflux temperature in a mixture of 34.5 g (1.42 mol) magnesium shavings and 215 ml absolute Dropped in diethyl ether. Stir another 30 Minutes after reflux and then drips like this prepared Grignard solution at room temperature with stirring in a solution of 218 g (1.42 mol) 1-chloro-1- (chloroacetyl) cyclopropane in 712 ml absolute diethyl ether. The reaction mixture is stirred for a further 4 hours at 25 ° C., then with  100 ml of glacial acetic acid are added and poured onto water. The organic phase is separated off. The watery Phase is extracted with diethyl ether. You wash the combined organic phases in succession aqueous sodium bisulfite solution and water, dries then over sodium sulfate and concentrated by stripping of the solvent under reduced pressure. This gives 358.6 g (90% of theory) on 1-chloro-2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) propan-2-ol in the form of an oily product.

1 H-NMR (200 MHz, CDCl₃):
δ = 0.78-1.30 (m, 4H), 3.16 (d, 1H), 3.67 (d, 1H), 3.73 (d, 1H), 4.15 (d, 1H) , 7.10-7.50 (m, 4H) ppm.

To 279.7 g (1 mol) of 1-chloro-2- (1-chloro-cyclopropyl) - 3- (2-chlorophenyl) propan-2-ol are used at temperatures between 20 and 30 ° C with stirring inside 234 g (1.3 mol) of a 30% strength by weight over 3 hours added methanolic sodium methylate solution. When the addition is complete, the reaction mixture is opened 40 to 50 ° C heated and 2 hours at this temperature touched. Then you cool to 10 to 20 ° C, sucks off the precipitated solid and  washes it twice with 200 ml of methanol. The Filtrate is at 40 to under reduced pressure Concentrated at 50 ° C. This gives 311 g of a product that is made up of 75% 2- (1-chloro-cyclo propyl) -2- (2-chlorobenzyl) oxirane. The yield is then calculated to 96% of theory.

A solution of 279.7 g (1 mole) of 1-chloro-2- (1-chloro cyclopropyl) -3- (2-chlorophenyl) propan-2-ol in 250 ml of methanol is stirred at 30 to 35 ° C. in portions with 207 g within 30 minutes (1.5 mol) potassium carbonate added. After finished The reaction mixture is added for a further 2 hours Stirred at 35 ° C and then cooled to 20 ° C. The fancy Solid is suctioned off and twice with washed 100 ml of methanol. The filtrate is concentrated under reduced pressure at 40 to 50 ° C. This gives 319 g of a product the 73.6% from 2- (1-chloro-cyclopropyl) -2- (chloro-benzyl) -oxirane consists. The yield is calculated then 96.5% of theory.

Example 2

To a mixture of 150 ml n-butanol, 50 g (1 mol) Hydrazine hydrate and 3 g (0.004 mol) of benzyl dodecyl dimethyl ammonium chloride in aqueous solution Temperatures between 55 and 60 ° C within 3 hours with stirring 121.5 g (0.5 mol) of 2- (1-chloro-cyclo propyl) -2- (2-chlorobenzyl) oxirane added. After finished The reaction mixture is added a further 3 Stirred at 55 to 60 ° C for hours, then to 10 to 20 ° C cooled and mixed with 50 ml of water. By adding of dilute, aqueous hydrochloric acid becomes a pH set from 7 to 8. The aqueous phase is separated off, and the organic phase is twice with each Washed 100 ml of water. After that, the organic Phase initially with 2.5 g (0.008 mol) of tetrabutylammonium bromide and then at 20 to 30 ° C with stirring inside of 30 minutes in portions with 104 g (1 mol) Formamidine acetate added. The reaction mixture is on Heated 110 to 120 ° C and 3.5 hours at this temperature touched. Then it is cooled to room temperature , adds 100 ml of water and, by adding dilute, aqueous sodium hydroxide solution to a pH of 7.5 to 8.0 a. The aqueous phase is separated off, and the organic phase is twice with 100 ml of water washed. This organic phase is concentrated at 70 ° C under reduced pressure and takes the remaining Residue at 65 ° C in n-hexane. After adding 10 ml n-Butanol is cooled uniformly within 3 hours to 10 to 20 ° C. The precipitated solid is suctioned off, washed twice with 100 ml of n-hexane and dried under reduced pressure.  

This gives 127 g of a product which 86.4% from 2- (1-chloro-cyclopropyl) -1- (2-chloro-phenyl) - 3- (1,2,4-triazol-1-yl) propan-2-ol. The yield is then calculated to be 70.3% of theory.  

Comparative example

In a mixture of 7 g of potassium hydroxide and 42 g (0.6 mol) 1,2,4-triazole in 100 ml of n-butanol are at 85 to 90 ° C. with stirring and under a pressure of 100 to 150 mbar within 30 minutes 123 g (0.508 mol) of 2- (1-chloro cyclopropyl) -2- (2-chlorobenzyl) oxirane was added dropwise. Man heats another 4.5 hours under a pressure of 200 up to 300 mbar at 85 to 90 ° C and thereby separates Water through a water separator. After that the reaction mixture is first cooled to 40 to 50 ° C., then mixed with 100 ml of water with stirring and Addition of 10% sulfuric acid neutralized. The solid 2- (1-chloro-cyclo propyl) -1- (2-chlorophenyl) -3- (1,3,4-triazol-1-yl) propan-2-ol is from the 40 to 50 ° C warm reaction mixture suction filtered and washed twice with 50 ml of n-butanol. The organic phase is separated from the filtrate and stirred with 100 ml of water. Then will the organic phase at 70 ° C under reduced pressure constricted. The remaining residue is at 70 to 80 ° C in 400 ml of methylcyclohexane. You cool evacuates uniformly to 20 ° C within 3 hours the precipitated solid, washed with 200 ml  Methylcyclohexane and dries at 40 to 50 ° C. To this This gives 90.4 g of a product which is 89.7% by weight from 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol. The yield is then calculated as 51.2% of theory.

Claims (9)

1. Process for the preparation of 2- (1-chloro-cyclopropyl) -1- (2-chlorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol of the formula characterized in that 2- (1-chloro-cyclopropyl) -2- (2-chloro-benzyl) oxirane of the formula with hydrazine hydrate in the presence of a diluent and, if appropriate, in the presence of a phase transfer catalyst and the resulting [1- (2-chlorophenyl) -2- (1-chlorocyclopropyl) -2-hydroxy] propyl hydrazine of the formula with formamidine acetate of the formula in the presence of a diluent and optionally in the presence of a phase transfer catalyst. 2. The method according to claim 1, characterized in that that when performing the first stage alcohols or uses ether as a diluent. 3. The method according to claim 1, characterized in that when performing the first stage at Temperatures between 20 ° C and 90 ° C works. 4. The method according to claim 1, characterized in that when performing the first stage on 1 mole of 2- (1-chloro-cyclopropyl) -2- (2-chloro-benzyl) oxirane of the formula (II) between 1.1 and 4.0 mol of hydrazine hydrate. 5. The method according to claim 1, characterized in that one when performing the second stage Alcohols or esters are used as diluents.   6. The method according to claim 1, characterized in that that when performing the second stage at Temperatures between 50 ° C and 130 ° C works. 7. The method according to claim 1, characterized in that that for 1 mol of [1- (2-chlorophenyl) -2- (1- chloro-cyclopropyl) -2-hydroxy] propyl hydrazine Formula (III) between 2.0 and 4.0 moles of formadine acetate of formula (IV). 8. The method according to claim 1, characterized in that that the implementations in the first and second Performs stage as a one-pot reaction. 9. The method according to claim 1, characterized in that that the implementations in the first and in the second stage in the presence of a phase transfer catalyst carries out.