DE2351707A1 - Triforine fungicides - in purified active forms by synthesis or fractionation - Google Patents

Abstract

Conventionally produced triforine (I) consists of 3 optical forms, differing in fungicidal activity viz(-)(-)>> mes >(I) (-), in the ratio 25:50:25. The racemate ((-)(-), (+)(-)) is generally more sol. than the meso and is pref. extd. e.g. with 10% H2O in Me2Co or with DMF, giving (I) with >60, pref. 70-95% racemate. Alternatively the (-)(-) form may be synthesised by: (a) condensing piperazine with (+)(-)- CCl3CHClNHCHO (II), (b) resolving e.g. via. the l(+)-tartrate, (c) basifying (NaOH) to isolate the (-)-inter. (d) condensing with another mole of (II) (e) fractionation by solvent extn. as above, to give the pure (-)(-) and (+)(-) forms. Meso form, obtd. by either route, may be isomerised by heating at 40-110 degrees C in a solvent e.g. DMF and recycling.

Description

CM- 34 Dr Ho / sk

CELAMERCK GMBH & CO, KG, INGELHEIM AM RHEIN

Pesticides

The invention relates to levorotatory N, N ^f -bis (l-formamido-2,2,2-trichloroethyl) piperazine, its production and its use as a pesticide.

The substance ^ N'-Bis-U-formamido ^^^ - trichloroethyl) -piperazine (Triforine) is effective against a wide variety of phytopathogenic fungi. The manufacture and application this systemic fungicide is described in the German Offenlegungsschrift 1 901 421.

The triforine molecule contains two asymmetric carbon atoms, each with the same radicals, so that the synthesis of the active ingredient produces 50% D, L-triforine (mesoform), 25 % L, L-triforine and 25 % D, D-triforine.

Already in the German patent application P 23 06 623.1 the preparation and use of two isomers of the active ingredient Triforine are described. These two isomers

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differ in their solubilities as well as in the biological properties. It could be proven that the less soluble, biologically less active isomer is the meso form and the more soluble, Biologically more active isomers around the racemate, i.e. the mixture of 50% each of L, L, -triforine and D, D-triforine acts.

A cleavage of the triforine racemate in the two optically active components is not possible with conventional methods, e.g. the basicity of the active ingredient is so low that that stable salts cannot be produced with optically active acids. There are also attempts at fractional crystallization the active ingredient with optically active solvents because of the low solubility of Triforine narrow limits set.

In the present invention, a method will now be described, inter alia, of left-handed triforine in optically pure form or in enriched form.

The following synthesis scheme illustrates the production of (-), (-) - triforine

Ah

LJ

H ^C1

CCl, -C -NH-CHO

·> Ι
Acid acceptor Λ

(+), (-) _ Γ | ((+), (-) - »i-Iono-Triforine") H

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23517Ό7

H "■■ '

b;) .CGl ₃ -C-NH-CHO

j + 2

η: "■■■■■ - ^;

CGI, -C-H-CHO CCl ^ -C-NH-CHO

(■■ + Η '

H ... LX V) -CHOQG-CHQH) ο Ή .X (^) - (HOQC-CHQH).

.- C- A.

O H. ..-. Μ

CCl ^ -G-JiH-GHO .CCl ^ -C-NH-GHO

ι. 3 ι

IJ ■ .- "N

(-) - Γ '. "T" ■ ^; NaOH (-) - Ι

H. (HOOC-CHOH) ₀ H.

d) H.

CCl ^ -C-NH-CHO
Ii

(-) - Ι j + ■ (+.), - (-) - CCl, -CH-NH-CHO

H ^{L ±}

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H acid acceptor (-J-CCl, -C-NH-CHO

^D I. N

N "(+), (-) - CCl, - C - NH - CHO

e) (-J-CCl ₃ -C-NH-CHO

C] fract. Extraction / fractional crystallizate.

N ^ >

C +), (- J-CCl ₃ -C-HH-CHO

H H

I i

CCl ^ -C-NH-CHO CCl ^ -C-NH-CHO ³ I ³ I.

N N

I I

CCl ₃ -C-NH-CHO Cd, -C-NH-CHO

Piperazine is initially only on one nitrogen atom with (+), (-) - l, 2,2,2-tetrachloroethylformamide to (+), (-) - N- (l-formamido-2,2,2-trichloroethyl) piperazine (hereinafter referred to as "liono-Triforine") implemented. This connection owns only one center of asymmetry and still shows due to the unsubstituted secondary amino group of the piperazine

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sufficient basicity to obtain diastereomers Salts with optically active auxiliary acids. In principle, mono-triforine can be used to produce diastereomeric salts any optically active acids such as L (+) - lactic acid, D (+) - camphoric acid, D (+) - a-bromcamphor-7i-sulfonic acid, (-) - Ο, Ο'-dibenzoyltartaric acid, (+) - mandelic acid, (-) - mandelic acid, L (-) - malic acid, L - (-) - 5-pyrrolidinone-2-carboxylic acid can be used. However, it is particularly suitable as an auxiliary acid the L (+) - tartaric acid. It was found that the two diastereomeric hydrogen tartrates of Mono-rTriforine due to different tendencies towards the formation of solvates and the widely differing solubility of the solvates in excellent Yields and can be separated without great purification effort.

Solving the mixture of the diastereomeric hydrogentartrates in water to crystallize the (-) - mono-triforine-hydrogen tartrate obtained in a yield of over 90% sit _x an optical purity of 98% as the pentahydrate. By recrystallization from water, the optical purity over & 99t5 can be increased.

The aqueous filtrate contains the (+) - mono-triforine hydrogen tartrate, which is very easily soluble in water. After the water has been distilled off, it is obtained by treatment with 96 tigern ethanol. (-fO-Mono-Triforine-hydrogen tartrate as crystalline ethanol solvate with over 80 % yield and an optical purity of over 99 %.

The separated diastereomeric Morio-Triforine-hydrogen-tartrate can be changed by treatment with alkali - in aqueous solution - in the optically pure bases old specific rotations of Convert -63.0 ° or + 62.6 °. Here, too, is another No cleaning required.

In the next reaction step the optically pure (-) - mono-triforine is again with (+), (-) - l, 2 _f 2,2-T * trachloroethyl-

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formamid implemented. A mixture of 50% meso-triforine and 50% (-), (-) - triforine is obtained on this catfish. (Correspondingly, (+) - monoi »triforins each 50 Ji meso-triforins and (+), (+) - triforins.)

These mixtures are separated into the corresponding isomers by fractional crystallization or fractional extraction. The solubility of the left- or right-rotating triforine compared to meso-triforine, which is 2-6 times greater in many solvents, is used. As the solvent are particularly suitable methanol, acetone with the addition of water up to 20% _t tetrahydrofuran, acetonitrile and dimethylformamide .. Enrichment of (-) (-) - triforine 1st example, by extraction of the mixture of laevorotatory Trlforine and meso triforine 90 tiger aqueous acetone, boiling methanol, tetrahydrofuran or dimethylformamide (DMF) possible. Extraction with an amount of DMF that is not sufficient to completely dissolve the ionic mixture is a particularly preferred embodiment of the enrichment of (-), (-) - triforins, since DMF has good ventilation properties for linked-rotating triforins and, moreover, these Solutions can be used directly for the production of highly effective pesticides. If it is desired to isolate enriched levorotatory triforine as a solid, then the substance can be precipitated or win by distilling off the solvent in a vacuum by pouring amr DMF solution in water.

To isolate the optically pure isomers, it is advisable to first separate off the bulk of the meso form by selective extraction and to crystallize the enriched, optically active product with a content of approx. 65-90% of levorotatory triforine. Particularly suitable solvents for the recrystallization are methanol and acetonitrile.

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Mechanical selection can also be used to isolate small amounts of the pure isomers , since under certain conditions mesoform and optically active triforine are obtained in different, well-formed crystals. When a mixture of meosoform and (-), (-) - triforine crystallizes slowly from acetonitrile, meso-triforine, for example, crystallizes in the form of clear, colorless prisms, whereas the levorotatory triforine crystallizes out in the form of colorless tufts of needles.

For the practice of plant protection of particular

It is important that the three triforine isomers are very

have different fungitoxic effects against different phytopathogenic fungi.

The biological test of the three isomers showed a decrease in effectiveness "in the order

(-), (-) - Triforine >> Meso-Triforine> (+), (+) - triforine.

The most biologically active form by far is therefore the left-handed triforine. The process according to the invention for the production or enrichment of (-), (-) - triforins has made it possible to provide an active ingredient for plant protection that significantly exceeds the triforine isomer mixture in its action against phytopathogenic fungi.

For economic reasons, it is advantageous not to use the levorotatory Triforine in an optically pure form, but enriched to 45 to 95 % for the production of plant protection agents .

While ordinary technical triforine only about 25% ah laevorotatory isomer contains one Example 4 wins according to the present invention, even without further enrichment, a product with about 50% of (-) (-) - triforine. By a subsequent selective extraction accordingly

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Example 6 is a Triforine solution with an approximately 80-6 (-), (-) - Form containing active ingredient. The complex fractional crystallization is therefore only required when optically completely pure (-), (-) - Triforine is to be produced, which is suitable for use as a pesticide is not required.

Liquid formulations with enriched levorotatory Triforine as active ingredient are preferably produced by a high-percentage active ingredient solution obtained according to Example 6 in a suitable solvent, preferably in DMF, by adding auxiliaries, e.g. emulsifiers, if necessary further solvent and defoamer, is adjusted to the desired active ingredient content.

Solid formulations with pure or enriched (-), (-) - Triforine, for example suspension powder, granules, dusts are in a manner known per se by adding the usual auxiliary and carrier materials.

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Example 1:

a.) (π-). (- ^ N-il-Formamido ^^^ - trlchlorethylO-piperazine

To a solution of 86 g (1 mol) of piperazine in a mixture of 80 ml of 12.5 η hydrochloric acid (1 mol) and 800 ml Water at 3 - 5 ° C with stirring within about 30 minutes at the same time a solution of 220 g (1.04 mol) (+), (-) - 1,2,2,2-tetrachloroethylformamide in 400 ml of acetone and a solution of 140 g (1.03 mol) of sodium acetate trihydrate in 200 ml of water. the initially clear solution slowly becomes cloudy and a colorless, viscous precipitate settles out.

After a further 30 minutes of stirring at 3-5 ° C., a solution of 170 ml of 6 η sodium hydroxide solution is obtained at this temperature (1.02 mol) was added dropwise. In a vacuum · is at room temperature the acetone is distilled off. The precipitated crystals of N.N'-Bis-U-foraamido ^^^ - trichloroethyl) -piperazine (36.5 g) are suctioned off. The aqueous filtrate is saturated with about 500 g of sodium chloride, the Hydrochloride of the title compound separates out in crystalline form. It is suctioned off, the hydrochloride is dissolved in 1000 ml of water, optionally filtered from a minor insoluble. Portion and treated with 170 ml of 6 η sodium hydroxide solution while cooling (1.02 moles).

The colorless product which crystallizes out is filtered off with suction, washed free of sodium chloride with ice water and dried at a maximum of 50.degree. This gives 179 g (68.8% dlTh.) Of pure (+), (-) - N- (l-formamido-2,2,2-trichloroethyl) -piperazine, mp 133-134 ⁰ C..

The substance can be recrystallized from ethyl acetate without any further cleaning effect.

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b.) (-) -N- (l-Formamido-2.2.2-trichloroethyl) -piperazine-L (+) - hydrogen tartrate pentahydrate

156 g (0.6 mol) (+), (-) - N- (l-formamido-2,2,2-trichloroethyl) piperazine and 93 g (0.62 mol) L (+) - tartaric acid dissolved in 800 ml deionized water at 30 - 40 ° C. The solution is kept for about 24 hours at +5 ⁰ C .i'ian gieiBt the supernatant liquid carefully from the departing large, clear crystals, and the crystals are washed twice with as little ice water.

The residue is air-dried at room temperature.

138.9 g (92.5 % of theory) of (-) - N- (1-formamido-2,2,2-trichloroethyl) piperazine L (+) - hydrogen tartrate pentahydrate are obtained. [a] jjp: -21.7 ° (water; c = 6) (optical purity 98.1%).

A single recrystallization from 6 parts of water at a maximum of 50 ° C. gives the compound with an optical purity of 100 %; [a] Jp: - 24.8 ° (water; c = 6).

ber .:

C ₇ H ₁₂ Cl ₃ N C ₄ H ₆ O ₆ . 5 H ₂ O 6 C 27.4 found: 27.5 9 6 H. 5.6 5.5 9 6 N. 8.4 8.3? £ Cl 21.3 ' 21.2 ^ 3 ° ο / r
/ OW Q / U
70 ΓΙ % N % Cl

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c.) (-) - N- (l-formamldo-2.2.2-trichlorethylene) -plperazln

250 g (0.55 mol (-) - N- (1-foraamido-2,2,2-trichloroethyl) -piperazine-L (+) - hydrogen tartrate pentahydrate are suspended in 1500 al of water. With cooling and stirring are at approx. 5 ° C internal temperature 490 ml 2 N sodium hydroxide solution (0.98 mol) added dropwise. Then 700 κ table salt is added. stirs for 1 hour at 5 - 10 ° G, sucks the finely crystalline colorless precipitate and washes twice with 150 ml each time Ice water out. The product is stored at room temperature

Yield will 4.5 g (88.2 % of theory); M.p. 140-142 ° C, [α] | ³ : -63.0 ° (ethanol; c = 6) (optical purity 99.5%).

d.) Mixture of (+). (-) - N.N '~ bis- (1-formamido-2.2.2 ~ trichloroethyppiperazln (meso-trilforine) and (-). (-) - N. N'-Bi3- (1-formamido-2.2.2- trichlorethylene) pjperazine (inverting triforine)

To a suspension of 78.2 g (0.3 mol) (-) - Ν- (Ι-formamido-2 _t 2,2-trichloroethyl) piperazine in a mixture of 30.3 g (0.3 mol) and triethylamine 300 ml of ethyl acetate pa becomes a solution of 63.3 g (0.3 mol) (+), (-) - 1,2,2,2-tetrachloroethylformamide ^{at +4 0 C with stirring within about 20 minutes} dripped in 300 ml of ethyl acetate pa. Then stir another one

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Hour at a maximum of 5 ° C, sucks the colorless crystal mixture and washes out with 100 ml of Eesigester.

The dried, pulverized residue is digested with 600 ml of water, filtered off with suction and free of chloride with water washed.

The mixture of meso-triforine and. levorotatory triforine is dried in a vacuum at a maximum of 60 ° C. 115 g of triforine («A) are obtained; Mp * 175-176 (line); [ _a ] 23rd - 40.4 ° (DMF; c = 6) (isomer ratio of meso-triforine: levorotatory triforine = 51.5: 48.5).

The combined ethyl acetate filtrates are below 40.degree evaporated in vacuo. The semi-solid residue is with a mixture of 200 ml of water and 200 ml of methylene chloride shaken. The methylene chloride phase is separated off and stored at 0-10 ° C for about 20 hours. The educated Triforine precipitate is filtered off with suction, washed with water and methylene chloride and dried below 60.degree.

A further 6.8 g of melting point 173-175 ° (Z.) C = B) are obtained; [α] ²⁵ : -73.6 ° (DMF; c 6) (isomer ratio of meso-triforine: levorotatory triforine 12:88).

Total yield of triforine: 121.8 g = 93.4 % of theory

e.) Separation of (+). (-) - NN * -BIs- (I-formanido-2.2,2-trichloroethvl) piperazln and (-). (-) - N.N'-Bia- (1-formamldo -2 ₁ 2.2-trlchloräthvl) piperazine

I. Obtaining seed crystals

6 g of powdered B with an isomer ratio of 12:88 are dissolved in 135 »1 warm acetonitrile. the The solution is kept without agitation for 90 hours at room temperature. The mother liquor is carefully poured from the crystals formed and washed twice with acetonitrile.

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Colorless tufts of needles; Mp 173-175 ⁰ C (dec.) [Α] Jp:. -82.2 ° (IMF; c = 6) (isomer levorotatory triforine: Meso triforine 98.5: 1.5) by a further recrystallization from acetonitrile the levorotatory triforine is obtained with practically no contamination from the meso form.

O] ² Jj *: - 83.2 ° (DMF; c = 6; optical purity> 99 %) .

II) Separation of the main amount of isomer mixture

114 g of the mixture of meso-triforine obtained according to Example 1 d) and levorotatory Triforine (= A; isomer ratio 51 »5: 48.5) are finely pulverized and 5 min. heated to reflux with stirring with 580 ml of methanol p.a. The suspension becomes hot over a preheated Sucked off suction filter (residue * II A). That. Filtrate will made up to 580 ml with methanol p.a., again to the boil heated, possibly of a small proportion of undissolved The substance is filtered off while hot and concentrated in vacuo.

A crystalline residue of 59 g (= II B) is obtained [a] Jp: -63.8 ° (DMF; c «6) (isomer ratio of levorotatory Triforine: Meso-Triforine: 76.5: 23.5).

58 g of II B are dissolved in 700 ml of boiling methanol p.a. The warm solution is mixed with meso-triforine (for extraction see below) and inoculated for 24 hours at room temperature kept. The methanol solution is poured from the precipitated crystals, which mainly consist of mesoform, and the solvent is distilled off in vacuo.

This leaves 35.9 g of already highly enriched (-),. (-) - Triforine back (= II C). O] Jp: - 74.0 ° (DMF; c ■ 6) (. Isomeric ratio of levorotatory triforine: meso-triforine «89 j 11).

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30 g of powdered II C are dissolved in 600 ml of boiling acetonitrile; the solution is inoculated with seed crystals of pure (-), (-) isomers obtained according to Example 1 e) I and stored for 72 hours at room temperature. That Crystals are filtered off with suction and washed with acetonitrile and purified twice more in the same way by recrystallization from acetonitrile.

This gives 8.6 g of pure (-) (-) - triforine mp 176-177 ⁰ C (dec.).. [a] j5 ^2: -83.0 ⁰ C (DMF; c '6) (optical purity> 99%).

R _f - ¥ erfc 0.50 (chloroform / methylglycol 9: 1 on silica gel) ^C 10 ^H l4 ^C1 6 ^N 4 ° 2 " ^{over # i 27 '60} * ^C - ^{eef # i 27} ' ⁷² * ^C

3.24 SH 3.50 % H.

12.88 % N 12.75 % N

48.91 % Cl 49.15 % Cl

The residue II A of the methanol extraction is again extracted with 300 ml of boiling methanol and then with 500 ml of boiling acetonitrile. The leftover Product is optically inactive and practically pure meso-triforine. The product can boiling from 150 parts Acetonitrile are recrystallized.

Mp .: 180 ° C (decomp.) J [α] ²³ : 0 ° (DMF; C = 6) R _f value 0.57 (chloroform / methylglycol 9: 1 on silica gel)

^c 10 ^H l4 ^nl 6 ^N 4 ° 2 calc .: 27.60 Ji C found .: 27.77 % C

3.24 % H 3.38 # H

12.88.Jf N 12.61 % N

48.91 % Cl 48.75 % Cl

Analogously, dextrorotatory triforine can also be obtained from (+) - N- (1-form aBido-2,2,2-trichloroethyl) piperazine and D, L-1,2,2,2-tetrachloroethylformamide. You get first the isonerene mixture with a spec. Rotation of + 38.4 ° (in DMF), from which fractionated crystalline

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sation pure "(+), (+ J-N.N'-Bis-U-formainido-Z, 2,2-tri chloroethyl) piperazine can be isolated.

Mp .: 174-175 ° C (decomp.) [Ajjp _: + 83.7 ° (DMF, c »6) (optical purity> 99.5%)

R _f value 0.50 (chlorine form / methylglycol 9: 1 on silica gel) Example 2

Enrichment of (-), (-) - NN ^t ~ bis ~ (l-formamido ~ 2.2 «2- trichloroethyl) piperazine

130 g (0.3 mol) of a finely powdered mixture of (-), (-) - triforine and Me sο-triforine ([<x] jp >> -40.2 °; isomer ratio of levorotatory) prepared according to Example 1 d) triforine t meso triforine 48: 52) are stirred 20 ⁰ C with 150 ml of dimethylformamide for two hours at 40 ° C and then for two hours at +. The suspension is filtered off with suction and the filter cake is washed twice with 10 ml of DMF each time. The residue is suspended in 200 ml of water, filtered off with suction, washed with water and dried below 60.degree.

53.1 g of substance with a melting point of 176-178 ° C. (decomp.) Are obtained [a] ² f5: -4.7 ° (DMF, c = 6) (isomer ratio of levorotatory triforine: meso-triforine = 5.5: 94.5).

The combined DMF filtrates totaling 188 ml contain 76 g = 40.5 % w / v of triforine with an isomer content of 78.5% levorotatory triforine and 21.5 % mesoform. Extraction yield of (-) »(* -) - form: 96 % of theory (The isomer ratio was determined densitometrically.)

The DMF solution with enriched (-), (-) - Triforine can can be processed directly into liquid crop protection agents (see example 3).

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To isolate the enriched levorotatory form as a solid, 94 ml of the DMF solution are stirred into 1500 ml of cold water. After 15 minutes of stirring, the precipitated material is filtered off, washed with water and dried below 60 ⁰ C. 37.2 g of triforine with a melting point of 174-176 ° C. (decomp.) Are obtained

[cc] Jp: -65.2 ° (DMF; c = 6) (isomer ratio <levorotatory Triforine: Meso-Triforine = 78:22).

Example 3 Solution concentrate

37.1 ml of the 40.5% strength solution obtained according to Example 6 and enriched with levorotatory triforine are mixed with 10 g of isopropylamine salt of dodecylbenzenesulfonic acid and 3 g of isohexadecanol. It is made up to 100 ml with N-methylpyrrolidine and in this way a liquid formulation is obtained with a triforine content of 15 % w / v. Isomer ratio (-), (-) - triforine: meso-triforine = 78.5: 21.5.

The isomer ratio is after 4 months of storage at 22 - 28 ° C unchanged.

The solution concentrate can be brought to the required application concentration by diluting with water.

Example 4

Composition:

0.05 % (-), (-) - Triforine ([a] ^ ³ : - 82.5 °; optical purity 98.5%)

0.10 % sesame oil

10.00 % dimethylformamide

89.85 % Frigene

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Example 5 Suspension powder Composition:

30 % (-), (-) - triforine ([oc] £ ³ : -74.0 °; optical purity 89 %) u

50 % kaolin 10 % colloidal silica 9% lignin sulfonate 1 % sodium tetrapropylene benzene sulfonate

Instead of (-), (-) - triforines with an optical purity of 89 % , triforines with a higher or lower content of the pure levorotatory form, especially the pure isomer, can also be used.

By grinding the constituents, a suspension powder is obtained which can be diluted with water to the required concentration.

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Claims (5)

- 18 claims 1. (-), (-) - N, N ^l -Bis- (l-formamido-2,2,2-trichloroethyl) piperazine. 2. Pesticides, characterized by a content of the compound according to claim 1. 3. Use of the compound according to claim 1 for combating phytopathogenic fungi. 4. Process for the preparation of the compound according to claim 1, characterized in that there is a mixture of (_), (_) _ N, N · -BIs- (I-formamido-2,2,2-trichloroethyl) -piperazine and (+), (-) - N, N'-BIs- (I-formamido-2,2,2-trichloroethyl) piperazine isolate the left-handed connection by a) the isomer mixture by fractional extraction and / or fractional crystallization or b) separating the crystals of one isomer by mechanical selection. 5. A process for the preparation of pesticides according to claim 2, characterized in that the active ingredient processed with customary auxiliaries and / or carriers in customary formulations. 509817/1201