DD284009A5 - PROCESS FOR PREPARING (AS, 1'R) -3- [N- (ACYL) -N- (3-CHLOROPHENYL)] - AMINO-TETRAHYDRO-2-FURONES - Google Patents

Abstract

The invention relates to a process for the preparation of *! -Amino-tetrahydro-2-furanones. The multi-step process for the preparation of *! -Amino-tetrahydro-2-furanones of the formula wherein the substituents having the meaning given in the description is that an α-phenylamino-g-butyrolactone is oxidized to a * with this acylating a carboxylic acid halide or carboxylic anhydride wherein X is chlorine, bromine or the radical 3COO, the resulting product is hydrogenated in the presence of enantioselective catalysts with hydrogen to give a * *! -ammonium tetrahydro-2-furanone, the hydrogenated product by chlorination into the diastereomeric mixture * * of the *! -amino-tetrahydro-2-furanones of the formula I and from this the enantiomer * is isolated by crystallization from a solvent. The * shows increased microbicidal activity over the isomer mixture. Formula (I) {Production Method; *! -amino-tetrahydro-2-furanone; Oxidation; acylation; hydrogenation; chlorination; Crystallization, microbicidal activity}

Description

284 O 09

Process for the preparation of (aS; 1'R) -3- /. N- (acyl) -N- (3-chlorphenyl27-araino-tetrahydro-2-furanones

Anv / endunKapebiet the invention

The present invention relates to a process for the preparation of milcrobicidally active (aS; 1'R) - and of (aR, 1'R; aS, 1'R) -3-Z ~ N- (acyl) -N- (3 chlorophenyl) _> _7-amino-tetrahydro-2-furanones, new, in part milcrobicidal active / intermediate intermediates, microbicidal agents containing these active substances and the use of these agents as microbicides in crop protection.

Characteristic of the known state of the art

Some substituted anilides known as microbicides contain centers of asymmetry and can accordingly occur as stereoisomers.

The 3- / ~ N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl) -7-amino-tetrahydro-2-furanone known from DE-OS 2,804,299 (= GB-1,577,702) as microbicide of the formula Ia

(Ia)

-1a-

has the asymmetry center indicated by % as the structure channel. It can be cleaved alo racemate in the usual way in optical antipodes, the different configurations have different strong microbicidal action.

In addition, DE-OS .2,004,299 does not provide any information on further isomerism possibilities outside the I'uranonring in the context of the broad chemical scope there.

In the case of the compound of the formula I obtainable conventionally as a roemate, however, a single enantiomeric pair is present not only on the basis of asymmetric substitution on the labeled * C atom, but a mixture of 4 isomers, ie. of two diastereomeric pairs of enantiomers.

The reason for this is that besides the asymmetric center mentioned, the molecule also has one, through the, chiral axis (Π).

has conditional rotational isomerism (atropisomerism) caused by the asymmetric chlorine substitution of the rotationally-disabled 2,6-dimethylphenyl ring. The prepared according to DE-OS 2,804,299 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone proves to be separable by adsorption chromatography or crystallization diastereomer mixture , which consists about 50% each of two at 140 ° or 115 ° melting diastereomeric Enantiomerenpaaren. These two diastereomeric pairs of enantiomers can be cleaved in the usual way into optical antipodes. From the diastereomeric pair of enantiomers melting at 140 ° C., the enantiomers (aS.I'S) - and (aR, 1'R) -3- (N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] -amino-tetrahydro-2-furanone, from the melting at 115 ° C diastereomeric enantiomeric pair, the enantiomers (aR.l'S) and (aS.l'R), for example, be isolated by chromatography on an optically active phase.

The enantiomer (aS, 1'R) -3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] amino-tetrahydro-2-furanone has a very greatly enhanced microbicidal activity with an unexpectedly high duration of action against the diastereomeric mixture of the formula Ia.

Also by chlorination of the (1'R) -3 - [(N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone of the formula Ha

The N-adjacent asymmetric carbon atom in the 3-position of the lactone ring is denoted by (I ¹ R) or (I ¹ S) for the configuration specification.

-3-

(Ha),

available Diastereomerengemisch (aR, 1'R; aS, 1 'R) -3- / N- (Uethoxyace tyl) -W- (3-chloro-2,6-dimethyl phenyl) _7-amino-tetrahydro-2-furanone shows a significant increase in the microbicidal activity compared to the diastereomeric mixture obtainable according to DE-OS 2,804,259, the extent of which is lower than in the case of the (aS, 1'R) enantiomer.

For the preparation of the (aS, 1'R) enantiomer or the diastereomer mixture (aR, 1'R; aS, 1'R) of 3- / ~ ^ ^T - (methoxyacetyl) -N- (3-chloro-2,6- dimethylphenyl) _7-amino-tetrahydro-2-furanone or (1'R) -3- / ~ (N- (methoxyacetyl) -N ~ (2,6-dimethyl-i-phenyl) J7-amino-tetrahydro-2 -furanons, however, no methods are known from the literature.

Object of the invention

The method according to the invention opens up the interesting entry from the technical-economic point of view to highly active stereoisomers and their mixtures, in particular to the diastereomeric table (aR, 1'R; aS, 1'R) and to the enantiomer (aS, 1'R) of FIG - / ~ N- (acyl) -N- (3-chloro-2,6-d-imethylphenyl) __ 7-amino-t et rahydro-2-furanone «

The less effective enantiomer (aR, 1'R) obtained as a by-product of the process according to the invention can be used according to the invention

-3a-

valuable Diaatereomerengomiach (aR, 1'R; aS, 1'R) of 3- (acyl) -N- (3-chlorophenyl) _7-amino-tetrahydro ~ 2-furanone 3 thermally be isomerized and used as such again in the manner described (recycling).

In the absence of enantioselective preparation processes, the diastereomer mixtures and enantiomers mentioned here, which because of their microbicidal activity were only able to be produced with the aid of expensive methods which are unsuitable for industrial use.

Explanation of the essence of the invention

It is an object of the present invention to provide a superior process for preparing the (aS, 1'R) enantiomer or diastereomeric mixture (aR, 1'R; aS, 1'R) of 3- / / N- (methoxyacetyl) -N - (3-chloro-2,6-dimethylphenyl-2,7-amino-tetrahydro-2-furan or (1'R) -3- / (N- (methoxyacetyl) -N- (2,6-dimethyl-ρ-tienyl) __7-amino-tetrahydro-2-furanone microbicidal active substances.

It was found that the isomer mixture (aS, 1'R; aR, 1'R) of 3- _i / "" N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl) __ 7-aininotetrahydro- 2-furanone can be prepared by a multistage enantioselective synthesis and that it is to be separated into the two enantiomers (aS, 1'R) and (aR, 1'R) by crystallization.

The enantioselectivity is due to asymmetric hydrogenation of an intermediate cyclic enamide in the presence of enantioselective catalysts. Enantioselectivity is defined as the preferred formation of one of the two possible enantiomeric reaction products, in this case the hydrogenation reaction products.

By selecting suitable catalysts, the formation of the de ·. preferred from the point of view of the invention of more valuable enantiomer.

Thus, the object of the present invention is a process for the preparation of (aS; 1'R) -3- [N- (acyl) -N- (3-chlorophenyl)] - amino-tetrahydro-2-furanones of the formula I.

° \ CL R ι N: 0

\ a ^% -H- K (i).

wherein

R 1 and R 2 independently of one another are methyl or ethyl and R 3 is methyl, chloromethyl, methoxymethyl or cyclopropyl, where

a) an α-phenylamino-γ-butyrolactone of the formula V

sC V?

wherein Ri and R2 are as defined above, to give a 3- (phenylamino) -2,5-dihydro-2-furanone d, Formula IV

wherein Ri and R2 have the abovementioned meaning, oxidizes this b) with a carboxylic acid halide or carboxylic anhydride of the formula VI

^R3 ~ jf ^x '

wherein R 3 has the meaning given under the formula I and X is chlorine, bromine or the radical R 3 COO-, to give a 3- [N- (acyl) -N- (phenyl)] -. 'nino-2,5-di ^v »ydro-2-furanone of formula III

~> - < ^Xj

in which R ₁ , R ₂ and R ₃ have the abovementioned meaning, acylated,

c) the resulting product in the presence of hydrogen donating enantioselectivity with hydrogen to give a (I ¹ R) S-fN-iAcyD-N-Cphenyl ")] amino-tetrahydro-2-furanone of formula II

hydrogenated

d) the hydrogenated product by chlorination in the diastereomeric mixture (aR.l'R; aS.l'R) of the 3- [N- (acyl) -N- (3-chlorophenyl)] - amino-tetrahydro-2-furanones of formula I transferred

e) and from the enantiomer (aS.l'R) isolated by crystallization from a solvent.

The invention also relates to the entire process and the individual Verfahrensgeschritf.e, wherein the intermediates of formulas II, III, IV and V can be optionally isolated; but it also relates to the new intermediates of formulas III and IV. The intermediate of the formula IHa

284

009

CH ₃

has microbicidal properties and is therefore also to be emphasized as an active substance.

The process is preferably carried out using those compounds of the formulas II to VI in which R 1 and R _{2 are} methyl, R _{3 is} methoxymethyl and X is chlorine. This results in the compound of the formula Ia.

A preferred embodiment of the inventive oxidation of the compounds of formula V to the compounds of formula IV is the reaction with manganese dioxide as the oxidant in a solvent at A0-140 ° C. The oxidation in toluene at 85-112 ⁰ C, or in diethyl ether is particularly preferred.

Also preferred is the embodiment of the oxidation with a CerIV compound as the oxidizing agent.

A further preferred embodiment of the oxidation of the compounds of formula V is carried out with a peroxide or a peracid as the oxidant in a solvent at -10 ° to + AO ⁰ C under atmospheric pressure and leads to the corresponding [N- (hydroxy) -N- (2 , 6-dialkylphenyl)] - amino-tetrahydro-2-furanone derivative. The latter is converted by dehydration into the compound of formula IV. The oxidation with m-Chlorperbenzoesätire as the oxidant in tetrahydrofuran at 0-10 ⁰ C is particularly preferred. The Wasserabsjiltung can be effected by addition of a dehydrating agent, such as basic alumina.

In carrying out the oxidation with m-chloroperbenzoic acid on a larger scale, the tetrahydrofuran can be advantageously replaced by other suitable solvents. As such solvents are halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as dichloromethane mentioned.

The acylation of the compound of the formula IVa with an excess of 50-500% of theory the compound of formula VIa to the compound of formula IIIa, optionally in the presence of a solvent such as toluene, with the output of the by-product hydrogen chloride by boiling under reduced pressure at 40-60 ⁰ C represents a bevorugte embodiment of the acylation step of the inventive method ,

A preferred embodiment of the inventive enantioselective hydrogenation of the compound of the formula IIIa to the enantiomer (I ¹ R) of the compound of the formula Ha is carried out in the presence of catalytic amounts of rhodium compounds of the formula VII or VIa

[XRhYZ] (VII) or [XRhY] ®A ^G (VIIa)

wherein X is two olefin ligands or a diene ligand, Y is a chiral diphosphine whose secondary phosphine groups are linked by 2-4 C atoms and which forms a 5-, 6- or 7-ring together with the Rh atom, or Y. Chiral diphosphinite whose phosphinite groups are linked via 2 C atoms and which together with the Rh atom forms a 7-membered ring, Z is chloride, bromide or iodide, and A represents the anion of an oxygen or complex acid, in one Alcohol as solvent, below 0.1-150 bar at -20 to + 7O ⁰ C. Particularly preferred is the implementation of the hydrogenation in the presence of 0.002-10 mole percent bis-norbornadienyl-rhodium (I) tetrafluoroborate and (4R, 5R) - (-) - 4,5-bis (diphenylphosphinomethyl) -2,2-dimethyl-l, 3-dioxolane, based on the compound of formula IHa, in methanol under 1-70 bar at 0-50 ⁰ C.

A likewise preferred embodiment of this enantioselective hydrogenation is carried out in the presence of catalytic amounts of a Ru [(R) -2,2'-bis (diarylphosphino) -l, 1'-binaphthylj salt of the formula VIIIa or a Ru [(S) -2 , 2'-Bis (diarylphosphino) -1,1'-binaphthylj salts of formula VIIIb

2 z

(VIIIb)

in which R _{1 is} an unsubstituted or monosubstituted by C ₁ -C ₁ -alkyl or methoxy phenyl radical or the 1- or 2-naphthyl radical and Z is either an anion of the formula R 5 COO, wherein R 5 is C 1 -C 6 -alkyl or CF 3 or the trifluoromethanesulfonate radical Anion means, in an alcohol solvent, below 0.1-130 bar at -20 to +70 ⁰ C. Particularly preferred is the implementation in the presence of 0.002-10 mole percent of Ru [(R) -or (S) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthylj-diacetate, based on the compound of formula IHa, in methanol at 1-70 bar at 0-50 °.

As a chlorinating agent in the compounds of formula II to the compounds of formula I is preferably elemental chlorine.

In the isolation of the (aS, l'R) enantiomer of the formula Ia is preferred as the solvent methyl ethyl ketone.

The present invention also includes a process for the preparation of the diastereomer mixture (aR.l'R; aS.l'R) in the ratio of 1: 1 of the formula I, which differs from the just described procedure only in that after chlorination of the Compound of Formula II resulting Diastereomerengemisch instead of Abtreni-jng of aSjl'R enantiomers, is isolated as a mixture of diastereomers. Prefers

is thereby the preparation of the diastereomer mixture (aR.l'R; aS.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone of formula Ia.

Likewise provided by the present invention is a process for preparing the diastereomer mixture (aS.I'R;aR.l'R) of the formula Ia by heating the enantiomer (aR.I'R) of the same compound to 160-180 ⁰ C during 1- 3 hours. According to the invention, these processes are preferably carried out in the presence of tetrabutylammonium bromide.

The oxidation according to the invention of the known compounds of the formula V to the compounds of the formula IV, which can also be regarded as a dehydrogenation of an amine, is likewise novel, the resulting compounds of the formula IV also being novel. The inventive acylation of these compounds with the carboxylic acid derivatives of formula VI to the new enamides of formula III has not been described. Methoxyacetyl chloride is preferred as the carboxylic acid derivative. The acylation may also, as usual, in the presence of equivalent amounts of bases, such as tert. Amines, to be performed. However, the yields to be achieved are massive. Also, the presence of catalytic amounts of Carbonsäuredialkylamiden, v.ie example, dimethylformamide instead of the tert. Amines only slightly increase the yield. The best results can be achieved according to the invention in the absence of bases or amides with excess acid chloride, wherein the byproduct hydrogen chloride from the (optionally under reduced pressure) boiling reaction mixture is driven off at a suitable temperature.

The intermediates of formula IV are novel and also form the subject of the present invention. The also new compounds of l'ormel III surprisingly proved to be fungicides and are also the subject of the present invention. Preference is given to the 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] - amino-2,5-dihydro-2-furanone of the formula IHa.

The starting materials of the formulas V and VI of the process according to the invention are known or can be prepared analogously to known methods.

The focus of the inventive method is the enantioselective preparation of the compounds of (I ¹ R) 3- [N- (acyl) -N- (phenyl)] - amino-tetrahydrofuran-2-furanones of the formula II starting from the corresponding a-phenyl amino-y-butyrolactones of the formula V.

For this purpose, according to the invention, this lactone is first oxidized (or dehydrated) to the corresponding 3- (phenylamino) -2,5-dihydro-2-furanone of the formula IV, the asymmetric center in the 3-position on the furan ring being eliminated. After acylation of the enamide of the formula IV to the enamide of the formula III, the latter is hydrogenated according to the invention to give (1'R) -3- [N- (acyl) -N- (phenyl)] -amino-tetrahydro-2-furanone of the formula II. As a result of this asymmetric hydrogenation, an asymmetric center is again formed in the 3-position of the furan ring, with the formation of the undesired I S enantiomer in favor of the desired I ¹ R enantiomer largely suppressed by suitable measures.

Asymmetric hydrogenation in the presence of rhodium catalysts as also defined under the formulas VII and VIIa, or in the presence of ruthenium compounds, as affinity under the formulas VIII and Villa

2 are described in the literature.

The novel asymmetric hydrogenation of the C =C double bond of the N-phenyl-enamiaan of the formula III is novel.

OverviewAmenitiesPicture literature:

[1] K. Koenig, The Applicability of Asymmetric Homogeneous Catalytic Hydrogenation in Asymmetric Synthesis, Vol. 5, S. Morrison (Ed.), Academic Press. N.Y., Inc., 1985, pp. 71 ff.

[2] S. Halpern, Asymmetric Catalytic Hydrogenation, ibid, p. 41 ff,

[3] H.B. Kagan, Chiral Ligands for asymmetric catalysis, ibid, p. 13-23.

- 11 -

This hydrogenation variant is preferably carried out in the presence of in each case 0.002-10 mol% of the rhodium catalysts of the formula VII or VIIa or of the ruthenium catalysts of the formula VIII or Villa, based on the compounds of the formula III used.

The reaction is preferably in solvents, such as alcohols, for example methyl, ethyl, propyl or butyl alcohol; Hydrocarbons, for example hexane, toluene, cyclohexane, methylcyclohexane; Ethers, for example diethyl ether, tetrahydrofuran, dioxane; or esters, for example ethyl acetate.

The catalysts of the formulas VII, VIIa are known from the literature (see review literature). Bis-norbornadienyl rhodium (I) tetrafluoroborate and (4R, 5R) - (-) - 4,5-bis- (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane are commercially available.

The catalysts of formula VIII and Villa are also known from the literature (T. Okta, H. Takaya, M. Kitamura, K. Nagai, R. Noyori, J. Org. Chem. 1987 , 52, 3174-3176; Okta, H. Takaya, R. Noyori, Inorg. Chem. 1988 , 27, 566-569).

The inventive asymmetric hydrogenation is carried out under a hydrogen atmosphere, preferably at 0.1-150 bar excess pressure. In particular, the pressure range of 1-70 bar is preferred. The reaction temperature is the range of -20 to +70 ⁰ C, especially that of 0 to 50 ⁰ C is preferred.

From the 3 · N- (acyl) -N- (phenyl)] -amino-tetrahydro-2-furanones, the diastereomer mixtures CaR ₁ I ¹ R; aS.l'R) are prepared from the 3- [N- (acyl) -N- (3-chlorophenyl)] - amino-tetrahydro-2-furanones of the formula I which are themselves useful as microbicides or in the enantiomers (aR.l'R) and CaS ₁ I ¹ R) can be separated.

Significant is still made in the context of the present invention Peststellung the surprising microbicidal activity of the compounds of 3- (phenylamino) -2,5-clihydro-2-furanones of the formula IV.

Ausführungsbeis piele

The process of the invention is further illustrated by the following examples.

Production Examples Example H1:

Preparation of the 3- / ~ N- (2,6-dimethylphenyl27-arnino-2,5-dihydro-2-furanone with manganese dioxide as the oxidant / f. Journal of Organic Chemistry, 2.9, 1540 (1964) _7

In a 75 ⁰ C warm solution of 53 g of potassium permanganate, in 330 g of water during 45 minutes simultaneously 43.6 g of manganese (II) sulfate Llonohydrat dissolved in 84 ml of water and 65 ml 40 % sodium hydroxide drips and then for 1 hour at 80 ⁰ C stirred. The precipitate is filtered off, washed neutral with hot water and at 125 ⁰ G in vacuo

- 13 -

dried. The resulting 48.3 g of manganese dioxide are suspended in 300 ml of toluene and boiled for 3 hours on a water. Then 13.6 g of 2- (2 ', 6'-dimethylphenylamino) -y-butyrolactone are added and the mixture is boiled overnight on a water separator. The solution is filtered and evaporated. After chromatography on silica gel with ether / hexane 1: 1 as eluent, 5.7 g (42% of theory) of 3- [N- (2,6-dinethylphenyl)] - amino-2,5-dihydro-2 -furanone as brown crystals (mp 80 ⁰ C). Mp after recrystallization from ether / hexane at 84-85 ° C.

Example H2: Preparation of 3- [N- (2,6-dimethylphenyl)] - amino-2,5-

dihydro-2-furanone with cerium (IV) ammonium nitrate as the oxidizing agent

To a suspension of 3.47 g (6.3 mmol) of cerium (IV) ammonium nitrate in 20 ml of methylene chloride is added 433 mg (2.1 mmol) of 2- (2,5-dimethylphenylamino) -ybutyrolactone. After stirring at room temperature for 18 hours, the orange reaction mixture is filtered and the filtrate is evaporated. After chromatography of the residue on silica gel with hexane / ethyl acetate 2: 1 as eluant, 190 mg (44 % of theory) of 3- [N- (2,6-dimethylphenyl) -] - amino-2,5-dihydro -2-furanone as a yellow-brown crystallizate, which was recrystallized from hexane / ethyl acetate 3: 1 (mp. 85-86 ° C).

Example H3a: Preparation of 3- [N- (2,6-dimethylphenyl) -amino-2,5-dihydro-2-furanone with m-chloroperbenzoic acid as oxidizing agent

To a solution of 61.5 g (0.3 mol) of 2- (2 ', 6'-dimethylphenylamino) -ybutyrolactone in 200 ml abs. Tetrahydrofuran is at ^{0 0} C within 30-60 minutes, a solution of 60.9 g (0.35 mol) of m-chloroperbenzoic acid in 200 ml of abs. Given tetrahydrofuran. The Heaktionsgut is stirred for 80 minutes at 0 ⁰ C and with 1 kg of basic alumina (ICN; act. I) filtered under ice-cooling of the template vessel. The alumina is eluted with tetrahydrofuran, the first 600 ml of eluate contain most of the formed 3- [N- (2,6-dimethylphenyl)] - amino-2,5-dihydro-2-furanone: 35.15 g in the form of white Crystals (57.6% of theory). Mp after recrystallization from hexane 85-86 ° C.

- 14 - 2 Q 4 OO 9

Example H3bi Preparation of 3- [N- (2,6-dimethylphenyl) ] amino-2,5-dihydro-2-furanone with m-chloroperbenzoic acid as oxidizing agent

To a solution of 61.5 g (0.3 mol) of 2- (2 ', 6'-dimethylphenylamino) -ybutyrolactone in 200 ml of dichloromethane at 0 ⁰ C within 30-60 minutes, a solution of 60.9 g ( 0.35 mol) of m-chloroperbenzoic acid in 200 ml of dichloromethane. The reaction mixture is stirred for 80 minutes at 0 ^° C. After filtration over a little basic alumina (ICN, Act I), the solvent is evaporated in vacuo and the residue is dissolved in 400 ml of tetrahydrofuran. The solution is filtered through 1 kg of basic aluminum oxide with ice cooling of the receiver vessel and worked up analogously to Example 3a. Result: 35.15 g of product in the form of white crystals (57.6% of theory)

Mp after recrystallization from hexane 85-86 ⁰ C.

Example HA : Preparation of 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] -amine-2,5-dihydro-2-furanone

10.2 g (50.2 mmol) of 3- [N- (2,6-dimethylphenyl)] - amino-2,5-dihydro-2-furanone, 40 ml (439 mmol) of methoxyacetic acid chloride and 40 ml of toluene are combined and boiled at 100-150 mbar for 48 hours Untsr reflux at 50-70 ⁰ C cooked. Subsequently, the reaction solution is evaporated, the residue dissolved in hexane / ethyl acetate mixture (2: 1) and chromatographed on silica gel. It is eluted with a hexane / ethyl acetate mixture (1: 2). The 3- [N- (methoxynecetyl) -N- (2,6-dimethylphenyl)] - amino-2,5-dihydro-2 obtained after evaporation of the solvent and recrystallization twice from hexane-ethyl acetate mixture (2: 1) furanone melts at 1O6-1O7 ° C.

Example H 5: Preparation of 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] amino-tetrahydro-2-furanone in the presence of bis-norbornadienyl rhodium (I) tetrafluoroborate and (4, 5R) - (c) -4,5-bis (diphenylphosphino) -2,2-hi methyl-1,3-dioxolane

0.9 g (4 mmol) of 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] -amino-2,5-dihydro-2-furanone is first dissolved in 10 ml in a 60 ml steel autoclave Methanol then 29 mg (0.08 mmol) of bis-norbornadienyl-rhodium (I) -

- 15 -

tetrafluoroborate and A4 mg (0.083 mmol) (4R, 5R) - (-) - 4,5-bis (diphenylphosphinomethyl) -2,2-dimethoxy-1,3-dioxolane, dissolved in 10 ml of methanol. The katal) hydrogenation with hydrogen is conducted at 20-22 ° C with an initial pressure of 33 bar hydrogen until the recording standstill (about 1 hour).

The residue obtained after filtration and ^evaporation: ickr.tand 98 in methylene chloride / methanol: dissolved 2 and chromatographed on silica gel. The product mixture obtainable after evaporation of the solvent is obtained in quantitative yield and comprises 90% of the enantiomers (I ¹ R) 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] -amino tetrahydro-2-furanone and 10% of its antipodes.

The pure (I ¹ R) EnantioiPdr is pure after recrystallization from hexane / Ethylmethylkaton 1: 1 75% yield.

Example Ho; Preparation of 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone in the presence of Ru [(R) - or (S) -2,2-bis (diphenylphosphino ] -l, l'-binaphthyl] -diacetate

0.45 g (2 mmol) of 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] - amino-2,5-dihydro-2-furanone is first dissolved in 10 ml in a 60 ml steel autoclave Methanol then 33.6 mg (0.04 mmol) Ru [(R) - or (S) -2,2-bis (diphenylphosphino) -l, 1'-binaphthylj-diacetate registered. The catalytic hydrogenation with hydrogen is carried out at 20-22 ⁰ C with an initial pressure of 30 bar hydrogen until the recording standstill (about 1 hour).

The residue obtained after filtration and evaporation is dissolved in methylene chloride / methanol 98: 2 and chromatographed on silica gel. The ProduktgemiCH obtained after evaporation of the solvent is obtained with quantitative yield and consists to 83% of the enantiomeric (I ¹ R) 3- [N- (methoxyacetyl) -N- (2,6-dimethylphenyl)] - amino-tetrahydro -2-furanone and 17% of its antipodes.

The pure (I ¹ R) enantiomer is purely available after recrystallization in 65.7% yield.

- 16 -

Example H7; Preparation of the mixture of (aR.l'R) - and (aS, l'R) -3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dinethylphenyl)] amino-tetrahydro-2 -furanone in the ratio of about 1:)

0.222 g of (l'R) 3- [N- (methoxyaoetyl) -N- (2,6-dimethylphenyl)] -amino-tetrahydro-2-furanone are dissolved in 30 ml of formic acid. 0.06 g of chlorine are introduced into the solution at room temperature in the presence of 5 mg of iron (IIl) chloride. The solution is stirred for about 1 hour, at room temperature and the solvent is evaporated off under reduced pressure. The residue is dissolved in ethyl acetate, the solution extracted with water, dried with sodium sulfate, filtered and evaporated. The dried mixture melts at 79-82 ° C, it contains about 50% each of the two isomeric title products.

Example H8: Preparation of (aS.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone from the mixture (aR .l'R) and (aS.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)) - amino-tetrahydro-2-furanone in the ratio of about 1: 1

0.5 g of the 1: 1 mixture (aR.l'R) and (aS.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino- tetrahydro-2-furanone are dissolved in 0.25 g of methyl ethyl ketone hot, in the cold with (aS, l'R) -3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] -amino-tetrahydro-2-furanone inoculated. After standing for 3 days at ^{0 0} C, the precipitated crystals are filtered off and dried. The crystals are pure (aS, l'R) -3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - aminotetrahydro-2-furanone.

Example H9: Preparation of the 1: 1 mixture (aR.I'R) and (aS.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino tetrahydro-2-furanone from the pure (aR, l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-β, 6-dimethylphenyl)] -arnino-tetrahydro-2-furanr α

0.2 g (aR.l'R) 3- [N- (methoxyacetyl) -N- (3-chloro-2,6-dimethylphenyl)] - amino-tetrahydro-2-furanone is mixed with 0.01 g of tetrabutylammonium bromide and held for 2 hours between 160-180 ⁰ C. The after cooling

- 17 -

a) b) c) 25% 40% 50% 5% 8th% 6%

12% 4% 15% 10% 25% 20%

CrisLallisierende reaction mixture is triturated with 1 ml of cold water, filtered and dried. The obtainable with quantitative yield crystallizate consists of the 1: 1 mixture of (aR.l'R) - and (aS, l'R) -3- [N- (methoxyacetyl) -N- (3-chloro-2,6 -ditnethylphenyl)] - amino-tetrahydro-2-furanone.

Formulation examples (% = weight percent)

F 1 Emulsion concentrates Compound of the formula IUa Ca-dodecylbenzenesulfonate castor oil polyethylene glycol ether

(36 moles of ethylene oxide 5%

Tributylphenoyl poly (ethylene glycol) ether (30 moles of ethylene oxide)

Cyclohexanone -

Xylene mixture 65%

From such concentrates, emulsions of any desired concentration can be prepared by dilution with water.

F 2 solutions

Compound of the formula IIIa ethyleneglycol monomethylather polyethylene glycol MG 400 N-methyl-2-pyrrolidone epoxidised coconut oil benzine (boiling range 160-190 ⁰ C) (MW = molecular weight)

These solutions are suitable for the preparation of microdispersions.

F 3 granules

Compound of formula IIIa kaolin

a) b) c) d) 80% 10% 5% 95% 20% - - - - 70% - - - 20% - - - - 1% 5% _ 94%

a) b) 5% 10% 94%

- 18 -

Highly dispersed silica 1%

Attapulgite - 90%

The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent is then evaporated in vacuo.

F 4 Dusts a) b)

Compound of Formula IIIa 2% 5%

Highly disperse silica 1% 5%

Talc 97%

Kaolin - 90%

Intimate mixing with excipients with the active ingredient gives ready-to-use dusts.

F 5 spray powder a) b) c) Compound of the formula IIIa 25% 50% 75% Na ligninsulfonate 5% 5% - Na-lauryl * i "lfat 3% - 5% Na Diisobutylnaphthalinsulfonat - 6% 10% Octylphenolpolyäthylenglykoläther (7-8 moles of ethylene oxide - 2% - Highly dispersed silicic acid 5% 10% 10% kaolin 62% 27%

The active ingredient is well mixed with the additives and ground in a suitable mill. This gives wettable powders which can be diluted with water to give suspensions of any desired concentration.

Biological examples

1. Action against Phytophthora infestans on tomato plants

a) Residual-protective action

Tomato plants were sprayed after 3 weeks of cultivation with a spray mixture (0.02% active substance) prepared from spray powder of the active ingredient as described above. After 24 hours, the treated plants were infected with a sporangia suspension of the fungus. The fungal attack was assessed after incubation of the infected plants for 5 days at 90-100% humidity and 20 ⁰ C.

b) Systemic effect

To tomato plants, after spraying for 3 weeks, a spray mixture prepared from wettable powder of the active ingredient as described above was poured [0.002% of active substance based on the volume of the soil]. Care was taken to ensure that the spray mixture did not come into contact with the aboveground plant parts. After 48 hours, the treated plants were infected with a sporangia suspension of the fungus. The fungal attack was assessed after incubation of the infected plants for 5 days at 90-100 % relative humidity and 20 ^° C.

The compound of the formula IIIa proved to be fully effective: the fungal attack was 0-5%.

2. P lasmopara viticola on vines (vine seedlings, cv. Gutedel (Chasselas) 3 pots each containing 1 plant / test substance)

a) Residual piotective leaf application

5-week-old vine seedlings are sprayed with a spray mixture prepared from the formulated test substance and infected 1 day later with a sporangia suspension (200Ό00 Sprorangien / ml) of P. viticola . The incubation takes place at 20 ^° C. in a greenhouse cabin; a 14 hour incubation with 100% rel. humidity

- 20 -

followed by A days with 75-85% and finally to the induction of PiIzsporulation one more night with 100%. After the 6-day incubation, the fungal infection is evaluated.

b) Systemic effect

5-week-old vine seedlings are infused with a spray mixture prepared from the formulated test substance. 3 days later, the plants with a spore suspension ₍ (200,000 sporangia / ml) of

P. viticola infects. Execution of the experiment as described under a).

With the compound of formula HIa the fungal infection was reduced to 0-5%.

3. Systemic action against Pythium debaryanum on Zea mays

The fungus was cultured on carrot shred nutritive solution and added to a soil-sand mixture. The so infected soil was bottled in flower pots and seeded with corn seed. Immediately after sowing, the test preparations formulated as wettable powders were poured into the soil as an aqueous suspension (20 ppm active ingredient of the formula IIIa based on the earth volume). The pots were placed on it for 3 weeks in the greenhouse at about 20 ⁰ C. The soil was kept evenly moist by a slight overshoot. In the evaluation of the tests, the number of accrued maize plants and the proportion of healthy and diseased plants was determined.

The number of accumulated and healthy plants was more than 90%.

Claims (11)

- 21 - Patent claim e 1. Process for the preparation of (aS; 1'R) -3- [N- (acyl) -N- (3-chlorophenyl)
amino-tetrahydro-2-furanones of the formula I. Ri and R2 are independent of each other methyl or ethyl and R 3 is methyl, chloromethyl, methoxymethyl or cyclopropyl, d adurch gekonnzeichnet that one a) a ci-phenylamino-y-butyrolactone of the formula V
· = · C-O wherein Ri and R2 are as defined above, to a 3- (phenylamino) -2,5-dihydro-2-furanone of the formula IV · = · ^Χ · -ο 12 wherein Ri and R2 have the abovementioned meaning, oxidizes this b) with a carboxylic acid halide or carboxylic anhydride of the formula VI R3-C-X (VI) - 22 - wherein R 3 has the meaning given under formula I and X is chlorine, bromine or the radical R 3 COO-, to give a 3- [N- (acyl) -N- (phenyl)] - amino-2,5-dihydro-2- furanone of formula III ' Y.S V - (: - < ^x - ^: you), wherein R 1, R 2 and R 3 are as defined above, acylated, c) the resulting product in the presence of enantioselectively active catalysts with hydrogen to give a (I ¹ R) 3- [N- (acyl) -N- (phenyl)).-amino-tetrahydro-2-furanone of formula II \ ₂
hydrogenated d) the hydrogenated product by chlorination in the diastereomer mixture (aR.l'R; aS.l'R) of the 3- [N- (acyl) -N- (3-chlorophenyl)] - amino-tetrahydro-2-furanones of formula I transferred e) and from the enantiomer (aS, l'R) isolated by crystallization from a solvent. 2. The method according to claim 1, characterized in that Ri and R2 are methyl, R3 is methoxymethyl and X is chlorine. 3. The method according to claim 2, characterized in that one the oxidation of the compound of formula Va in the compound of formula IVa -23- 28 A CH ₃ O CH ₃ O ^ · = · CO «= · CO • 'NH-v · ν · KH ·. 009 ^N CH ₃ ^N CH ₃ (Va) (IVa) with manganese dioxide as the oxidizing agent in a solvent at 40-1AO ⁰ C performed. A. A process according to claim 3, characterized in that one carries out the oxidation in toluene at 85-112 ° C. 5. The method according to claim 2, characterized in that one carries out the oxidation with a CerIV compound as the oxidizing agent. 6. The method according to claim 2, characterized in that one a) the compound of formula Va, claim 3, with a peroxide or a peracid in a solvent at -10 ° to + AO ⁰ C under atmospheric pressure to give [N- (hydroxy) -N- (2,6-dimethylphenyl)] oxidized amino-tetrahydro-2-furanone and the latter is converted by dehydration in the compound of formula IVa, b) the acylation of the compound of the formula IVa with an excess of 50-500% of theory the compound of the formula VIa to the compound of the formula IIIa , CH ₃ CH ₃ OCH ₂ CCl · '/ · 1 / ^X -i Ö ^N '~' v CCH ₂ OCH ₃ CH ₃ 0 Via IHa with loss of the by-produced hydrogen chloride by boiling under reduced pressure at A0-60 ° C, c) the hydrogenation of the compound of formula IHa to the enantiomer (I ¹ R) of the compound of formula Ha CH ₃ > · = · · 1 V. \ (Ha), ^N - (CCH ₂ OCH ₁ CH ₃ ö in the presence of catalytic species of rhodiuria compounds of formula VII or VIIa [XRhYZ] (VII) or [XRhY] ®ã ^east (VIIa) wherein X is two olefin ligands or a diene ligand, Y is a chiral diphosphine whose secondary phosphine groups are linked by 2-4 C atoms and which forms a 5-, 6- or 7-ring together with the Rh atom, or Y. Chiral diphosphinite whose phosphinite groups are linked via 2 C atoms and which together with the Rh atom forms a 7-membered ring, Z is chloride, bromide or iodide, and A represents the anion of an oxygen or complex acid, in one Alcohol as a solvent, below 0.1-150 bar at -20 ° to + 70 ⁰ C, d) the chlorination of the compound of formula Ha to the compound of formula Ia S Y \ =. ' Sy Ι / N _x / \ I ^Ν - (CCH ₂ OCH ₃ CH ₃ 0 with elemental chlorine and e) carrying out the isolation of the enantiomer (aS.l'R) of the formula Ia from methyl ethyl ketone as solvent. -25- 2 β 4 O 9 7. The method according to claim 6, characterized in that the oxidation with m-chloroperbenzoic acid as the oxidizing agent in tetrahydrofuran at 0-10 ⁰ C and the hydrogenation in the presence of 0.002-10 mole percent of bis-norbornadienyl-rhodium (I) tetrafluoroborate and (4R, 5R) - (-) - 4,5-bis- (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane, based on the compound of the formula IIIa, in methanol under 1-70 bar at 0- 50 ⁰ C performed. 8. The method according to claim 6, characterized in that the oxidation with m-chloroperbenzoic acid as the oxidizing agent in dichloromethane at 0-10 ⁰ C and the hydrogenation in the presence of 0.002-10 mole percent of bis-norbornadienyl-rhodium (I) tetrafluoroborate and (4R, 5R) - (-) - 4,5-bis- (diphenylphosphinomethyl) -2,2-dimethy1-1,3-dioxolane, based on the compound of formula IHa, in methanol at 1-70 bar at 0 -50 ⁰ C performed. 9. The method according to claim 2, characterized in that one a) the compound of the formula Va, claim 3, with a peroxide or a peracid in a solvent at -10 ° to + 40 ⁰ C under atmospheric pressure to N- [N- (hydroxy) -N- (2,6-) dimethylphenyl)] - amino-tetrahydro-2-furanone and the latter is converted by dehydration into the compound of formula IVa, b) the acylation of the compound of the formula IVa with an excess of 50-500% of theory the compound of the formula VIa to the compound of the formula IIIa CH ₃ OCH ₂ COCl · '\ } / C 0 CH ₂ OCH ₃ CH ₃ Via IHa with loss of hydrogen chloride by-produced by boiling under reduced pressure at 4O-6O ° C, hydrogenation of the compound of formula IHa, claim 6, to Enanticmeren (I ¹ R) of the compound of -26- 26 4 0 09 Formula Ha, claim 6, in the presence of catalytic amounts of a Ru / ~ (K) ~ 2,2 * -bis (diarylphosphino) -1,1'-binaphthyl_7-salt of the formula VIIIa or a Ru / "- (S) - 2,2'-bis (diarylphosphino) -1,1'-binaphthyl ^ / - salves of formula VIIIb 2 Z " ι ι ι (Villa) (VIIIb) ^R 4 ^R 4 ; R Ru 2 z wherein R denotes an unsubstituted or monosubstituted by C.sub.1-C.sub.4-alkyl or methoxy phenyl radical or the 1- or 2-naphthyl-1-ene and Z ~ entv / erd an anion of the formula Rp-COO.sup.j, in which R j - represents C j -CO- Alkyl or GF ^ or the Trifluormethanaulfonat anion, in an alcohol solvent, under 0.1-150 bar at -20 to + 70 ⁰ C and the chlorination of the formula Ha to the compound of formula Ia, claim 6, with elemental Chlorine performs. 10. The method according to claim 9>, characterized in that the hydrogenation in the presence of 0.002-10 mole percent of R \ x £ ~ (r) - or (S) -2,2'-bis (diphenylphosphino) -1,1 ' -Binaphthyl__7-diacetate, based on the compound of formula IHa, in methanol at 1-70 bar at 0-50 °. 11. A fungicidal composition, characterized in that it ala active ingredient 0.1-95 % 3-Z ~ N- (methoxyacetyl) -N- (2,6-dimethylphenyl) _7-amino-2,5-dihydro-2-furanone of Formula HIa, claim 30, together with a suitable carrier material. 12. A method for controlling plant-damaging microorganisms, characterized in that the plant or its location a microbicidally effective amount of 3- / ~ N- (methoxyacetyl) -N- (2,6-dimethylphenyl) __ 7-amino-2.5 dihydro-2-furanone of the formula IHa, claim 30 applied.