DD160416A5 - PROCESS FOR PREPARING 3- (N-ARYL-N-ACYLAMIO) -GAMMA BUTYROTHIOLACTONES - Google Patents

Abstract

The invention relates to a process for the preparation of 3- (N-aryl-N-acylamino) -y-butyrothiolactones which are suitable as fungicides. The method consists of cleaving the corresponding arylamino-y-lactone with a thiolate salt to obtain the corresponding arylaminothiolakancarboxylate salt, hydrolyzing the salt, and then acylating the acid to obtain the corresponding N-acyl-N'-aryl amino product. This product is then cyclized to recover the compound of interest. Optionally, the sequence of cycles of acylation and cyclization can be reversed.

Description

2310 58 7 - <-

Field of application of the invention

The invention relates to a process for the preparation of 3- (N-aryl-N-acylarnino) - (/ '- butyrothi.olactonen.

Characteristic of the known technical solutions

3- (N-Aryl-N-acylamino) - ^ - butyrothiolactones are known compounds having a fungicidal activity and are described for example in BE-PS 871 668. According to this BE-PS, the compounds via the amination (anilination) of 3-halo <A-butyrothiolactones and subsequent acylation with the corresponding acyl halo. genid produced.

There is also known a process for preparing such compounds by cleaving off the corresponding N-aryl-N-acylaminolactone analogs with a thiolate salt and then treating the resulting (N-aryl-N-acylamino) -carboxythioalkane product with phosphorus trichloride to close the ring.

The preparation of certain non-substituted thiolactones is further described by Truce et al. in "Journal of Organic Chemistry", Vol. 28, p. 964 (April 1963).

Object of the invention

The aim of the invention is to provide a further improved process for the preparation of 3- (N-aryl-N-acylamino) - (f-thiobutyrolactonen and the resulting intermediates in high yields.

23JIIR. 1981 * 942 654

58 7''- * -

Explanation d the essence of the invention

The inventive method consists in the following stages:

(a) contacting a 3- (aryl or subst.-arylamino) - / ^. butyrolactone or a 5-substituted derivative thereof with a thiolate salt under reactive conditions to obtain the corresponding 1- (aryl or substituted aryl) amino-1-thioalkanecarboxylate salt and acidifying the salt to obtain the corresponding carboxylic acid,

(b) contacting the product of step (a) with an acyl halide under reactive conditions to obtain the corresponding acylamino derivative and

(c) contacting the product of step (b) with a cyclizing agent which effects esterification of a saturated fatty carboxylic acid with a lower molecular weight primary alcohol to obtain the corresponding 3- (N-aryl or substituted aryl-N-acylamino ) C 1-8 -butyrothiolactone or a 5-substituted derivative thereof.

Optionally, the order of steps (b) and (c) may be reversed so that first the intermediate of step (a) is cyclized, followed by acylation.

An embodiment of the process according to the invention can advantageously be represented schematically by the following overall reaction equations:

231058 7 - '

HHR ²

I πα Il

Ar - Ν-4 - ί T. +. M (SR) -> Ar - N - CH - CH ₂ - CH - SR

I ² JLr ^{2 {1)} , '\

^ i (B) , ' c = o

(A)^ f / I (D.

/ O CR ¹ R

(I) + R ¹ CX > Ar-N-CH-CH ₂ -CH-SR

(Salt or Gaure) (C) (2) I ^

I,

OR ³ (H)

CyclisierunasmitteL

 (II) - - ^ Ar - N

(3)

^^ S

(III).

wherein Ar is aryl or substituted aryl having from t to 4 substituents selected from fluoro, chloro, bromo, iodo, lower alkyl or lower alkoxy, R is lower alkyl (preferably tertiary butyl), lower alkenyl (preferably allyl) or arylalkyl (preferably benzyl) .

R is lower alkyl, lower alkoxy, cycloalkyl of 3 to 6 carbon atoms (preferably cyclopropyl), lower epoxyalkyl of 2 to 6 carbon atoms, including one or two epoxy groups, lower alkenyl, lower alkenyloxy, hydroxy lower alkyl (preferably hydroxymethyl), haloalkyl of 1 to 3 halogen substituents and 1 to 6 carbon atoms (lower) lower alkoxyalkyl, lower alkylthioalkyl, phenylthio-lower alkyl, (preferably phenylthiomethyl), phenoxy-lower alkyl (preferably phenoxymethyl), substituted phenylthio-lower alkyl (

Ιό I

preferably substituted phenylthiomethyl) or substituted phenoxy-lower alkyl (preferably substituted phenoxymethyl) having one or two ring substituents selected from fluoro, chloro, bromo, iodo, lower alkyl or lower alkoxy, while

2 R is hydrogen, chloro, bromo, lower alkyl, phenyl or substituted phenyl having 1 to 2 substituents selected from fluoro, chloro, bromo or lower alkyl, typified, and

or 0

It

-CR ¹ '

1 '1

R is selected from the group of substituents given for R.

R is hydrogen or 0, where

M is an inorganic cation, preferably an alkali metal cation, while m is its valence, while X is chlorine or bromine.

Stage 1 of the process can be carried out in an expedient manner in that the corresponding compound

of the formula A having the desired Ar and R substituents is contacted with the thiolate of the formula B, preferably in a suitable organic solvent under reactive conditions.

Typically, this process is carried out at temperatures between about 20 and 200 ^° C., and preferably about 50 to 80 ^° C., for about 1 to 8 hours and preferably for about 1 to 4 hours. Typically, about 1 to 1.5 moles and preferably about 1 to 1.25 moles of the compound of formula B, based on the thiolate content, are employed per mole of the compound of formula A.

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-it

When an organic solvent is used, the solvent is generally only a solvent for Reactant A. Suitable inert organic solvents which may be used include, for example, dimethoxyethane, toluene, tetrahydrofuran, dimethylformamide, or the like, and compatible mixtures thereof. Preferably, dimethoxyethane is used as solvent; Typically, a ratio of about 1 to 3 moles of reactant A per liter of solvent used is maintained.

In general, the best results are achieved when the process is carried out at temperatures between about 50 to 80 ^° C using about 1 to 1.10 Mdl of B per mole of A in dimethoxyethane.

Suitable thiolates of the formula B which can be used are, for example, alkali metal thiolates, for example sodium 2-methyl-2-propanethiolate, potassium 2-methyl-2-propanethiolate, alkaline earth lithiolates, calcium bis (alkyl thiolates), ammonium thiolates, quaternary amine thiolates, for example tetramethylammonium thiolate , Benzylthiolate, or the like. When alkylmercaptides are used, tertiary alkylmercaptides are preferred over the secondary and primary alkylmercaptides in terms of yields, while secondary alkylmercaptides are preferable to primary alkylmercaptides. In general, best results are obtained using sodium 2-methyl-2-propanethiolate. In a preferred embodiment, the thiolate salt is prepared in situ via the reaction of the corresponding RSH mercaptan with an alkali metal alkylate, for example, sodium methylate.

The compounds of the formula A are known compounds and can be prepared by known methods, for example by reacting the corresponding aryl or substituted arylamine with the corresponding 3-chloro- or 3-bromobutyrolactone, and this, for example

Ιό Ι U Ό Ό / - * - * -

in U.S. Pat. No. 871,668 and in U.S. Patents 3,933,860 or 4,165,322.

The product of step 1 is the corresponding M salt of the acid of formula I. Prior to carrying out the second step of the process of the invention, it is preferable to remove any unreacted compound (A) present from the reaction product. This may conveniently be by extraction, since the compound (A) is generally insoluble in water while the compound (I) is soluble in water.

The salt (I) may then be reacted with the acyl chloride or bromide (C) corresponding to step 2 of the process of the invention or is preferably first hydrolyzed to the acid of formula I by treatment with a weak acid such as acetic acid. Optionally, the hydrolysis can generally be carried out in situ. The acid treatment offers an economic advantage and in some cases requires the production of a clearer acylation reaction product than in the case of a direct acylation of the salt (I). An economic advantage is achieved because the acid, for example, acetic acid, is substantially cheaper than the acyl halide (C). Therefore, if the salt (I) is directly acylated, then 2 moles of the acyl halide are required stoichiometrically per mole of the salt (I). By first hydrolysis of the salt (I) one of these Acylhalogenidmole is replaced by a cheaper acid mol.

In the second stage of the process, the salt of formula I or its acid is reacted with the corresponding acyl chloride of formula C under reactive conditions, preferably in an inert solvent and optionally in the presence of an organic scavenger base under reactive conditions. It has been found that this process stage gives very high yields of the product of formula II.

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acts. The acylated product of formula II also functions better in the cyclization reaction (step 3) than the corresponding secondary amine, probably due to the protection of the free NH group with an acyl group. The product is generally a mixture of the 1-carboxy acid and its anhydride, i. H.

Il

R ³ is CR ¹ '

depending in each case on the relative molar ratio of the reactants.

This process is typically performed at temperatures between about 0 and 120 ⁰ C for about 1 to 8 hours when a Abfängerbase is used. Lower temperatures are preferably maintained, typically between about 0 and 25 ° C. If no Abfängerbase used, higher temperatures are maintained, typically between ⁰ and 120 C to drive off the hydrogen chloride occurring as by-product as a gas. In general, about 2 to 2.5 moles and preferably 2 to 2.2 moles of acyl chloride (C) are used per mole of reactant I (salt) and about half that amount of acyl halide when the acid of formula I is used (ie about 1.0 to 1.5 and preferably 1.0 to 1.10 moles of acyl chloride per mole of acid I).

Suitable inert organic solvents which may be used are, for example, chlorinated hydrocarbons, e.g. Methylene chloride, ethyl acetate, dimethoxymethane, benzene, dioxane, tetrahydrofuran or the like, as well as compatible mixtures thereof. If the reaction is carried out in the presence of an organic scavenger base which reacts with the by-produced hydrogen chloride.

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triethylamine, pyridine, 2,6-lutidine, sodium carbonate or the like come into question as suitable scavenger bases.

The acyl chlorides and bromides (C) are known compounds and can be prepared by known methods or obvious modifications of these methods, for example by replacement of the corresponding substrates, solvents, etc. In general, it is preferable to use acyl chlorides

\  -. '

\. The last step of the process is preferably carried out by contacting the compound of formula II with a suitable cyclizing agent, preferably in a suitable inert organic solvent, under reactive conditions.

In typical Feiß this process is carried out at temperatures between about 0 ⁰ C and the reflux, and preferably above about 5 ° C for about 1/4 to 2 h, and preferably about 1/4 to 1 h. In general, about 1 to 5 moles and preferably 2 to 2.5 moles of reactant II are employed per mole of the cyclizing agent. The optimum temperatures and the optimal ratios of the cyclization agents vary depending on the particular cyclization agent used. If, for example, sulfuric acid is used as the cyclizing agent, then preferably only a relatively small amount is used. For example, if phosphorus trichloride is used as the cyclizing agent, it is preferable to use about 2 to 2.5 moles of the reactant II per mole of phosphorus trichloride.

Since water is by-produced, it is preferable to conduct the reaction under conditions in which water is removed from the reaction system, for example, by distillation or by use

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Of cyclization reagents, etc. that bind water.

Suitable inert organic solvents which can be used are, for example, chlorinated hydrocarbons, for example methyl chloride, ethyl acetate, benzene, diallyl glycols, for example 1,2-dimethoxyethane or the like, and compatible mixtures thereof. Typically, a solvent ratio of about 0.5 to 3 moles of reactant II per liter of solvent is maintained.

A very wide range of cyclization agents can be maintained. These reagents can be defined as those reagents which cause esterification of a saturated fatty acid on contact of the acid with a primary, low molecular weight alcohol. Suitable cyclizing agents which can be used are, for example, carboxylic anhydrides, for example, acetic anhydride, phthalic anhydride, acyl chlorides, for example, acetyl chloride, benzoyl chloride, trichloroacetic acid, p-toluenesulfonic acid, monoalkyl dihydrogen phosphites, for example, decyl dihydrogen phosphite, boron trifluoride etherate, sulfonic acid ion exchange resins, phosphorus trichloride, phosphorus tribromide, phosphoric acid, thionyl chloride, phosphorus pentachloride, sulfuric acid , Phosgene, oxalyl chloride, carboxylic acids or the like as well as compatible mixtures thereof.

Very good results are obtained when the process using 2 to 2.5 moles of the reactant II per mole of phosphorus trichloride in methylene chloride at temperatures between about. 5 and 15 ⁰ C is performed. Further, good results are obtained when acetic acid is used with a small amount of sulfuric acid as the cyclizing agent under reflux conditions.

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- 40 -

Optionally, the order of the acylation step and cyclization step can be reversed. This can be represented schematically by the following overall reaction equation:

/ _T v C yclislorungsmittel _v

(2a) (salt or acid)

O η

C - R ¹

(Ha) + R ¹ CCl ---> Ar-N

(3a)

wherein Ar and R have the meanings given above.

The steps (2a) and (3a) can be carried out according to the method described above in connection with steps (3) or (2). As in the case of the step (2), it is preferable to use the acid form of the compounds of the formula I as the starting material for the step (2a) and not the salt form.

In each of the process steps described above, it is, unless otherwise stated, preferable to separate the corresponding products of formulas I and II before the nurchführuno the next stage of the process. With the exception of the hydrolysis of the salt (I) to its acid, it is generally preferable to carry out the process according to the invention under essentially anhydrous conditions. The corresponding products of formulas I, II, Ha and III can be separated from the respective product reaction mixtures by any suitable purification method.

tr

Examples of suitable separation and purification methods are illustrated in the following examples, but it is to be understood that other suitable methods may be used, for example, by evaporation, extraction, crystallization, chromatography, distillation or the like.

It should also be noted that, given typical reaction conditions (eg, temperatures, molar ratios, reaction times, etc.), conditions may be met which are both above and below these ranges, but generally in these cases there are less economic advantages be achieved. The optimum reaction conditions (for example, temperatures, solvents, reaction times) may vary depending on the particular reactants, concentrations, etc., but can be determined by routine experimentation. "

The following terms have the meanings explained, unless stated otherwise. The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "alkyl" means straight-chain and branched alkyl groups. The term "lower alkyl" refers to both straight-chain and branched-chain alkyl groups having a total of 1 to 6 carbon atoms and includes primary, secondary and tertiary alkyl groups.

Typical lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, tert-butyl, n-hexyl or the like.

The term "alkoxy" refers to the radical R ¹ O-, where R ^{1 is} alkyl.

2310

^f - vs -

The term "lower alkoxy" includes alkoxy groups having 1 to 6 carbon atoms, for example, methoxy, ethoxy, tert-butoxy, hexoxy or the like.

The term "lower epoxyalkyl" refers to epoxyalkyl groups having 2 to 6 carbon atoms, for example, one or two oxy groups. Such groups include, for example, 1,2-epoxypropyl (ie, CH ₃ -CK ^ -An-); 2,4-epoxypentyl (ie, 4'-methyloxetanylmethyl; CHo-CH-CH ₉ ^ CH-CH ₀ -);

1,2,4,5-diepoxyhexyl (ie CH ₃ -CH - CH-CH ₂ -CH-ArH-) or the like.

The term "hydroxy-lower alkyl" includes groups of the formula HOR ¹ wherein R ^{1 is} lower alkyl. Mention may be made, for example, hydroxymethyl, 3-hydroxypentyl, 2-hydroxyethyl or the like.

The term "lower alkoxyalkyl" refers to R'OR "-, wherein R ¹ O is lower alkoxy and R" is lower alkyl.

The term "lower alkylthioalkyl" refers to the rest. R ¹ SR "-, wherein R 'and R" independently represent lower alkyl. Typical lower alkylthioalkyl groups are, for example, methylthiomethyl or 4-tert-butylthiohexyl.

The term "alkenyl" refers to unsaturated alkyl groups having one double bond and includes both straight-chain and branched alkenyl groups.

The term "lower alkenyl" refers to alkenyl groups of 2 to 6 carbon atoms. Typical lower alkenyl groups are, for example, allyl, but-3-enyl, 2-methylpent-4-enyl or the like.

The term "lower alkenyloxy" includes the groups of

5 5

Formula R 0-, where R is lower alkenyl.

239Ubo /

The term "ni'edrigalkeny] oxyalkyl" includes groups of the formula R OR '- where R is lower alkenyl and R' is lower alkyl. Typical lower alkenyloxyalkyl groups are, for example, allyloxymethyl, 2- (but-3-enyloxy) hexyl or the like.

The term "aryl" includes aryl groups having 6 to 12 carbon atoms, for example, phenyl and naphthyl.

The term "phenoxycycloalkyl" refers to groups of the formula Ph-O-R'-, where Ph is phenyl and R 'is lower alkyl. Examples are phenoxymethyl, phenoxyhexyl, 5-phenoxy-3-methylpentyl or the like.

The term "phenylthio-lower alkyl" refers to groups of the formula Ph-SR ¹ -, wherein Ph is phenyl and R ^{1 is} lower alkyl. Mention may be made, for example, phenylthiomethyl, phenylthioethyl, 4-phenylthio-1-methylbutyl or the like.

The term "substituted phenoxy-lower alkyl" refers to groups of the formula Ph'-O-R'-, wherein R 'is lower alkyl and Ph' is a phenyl group having 1 to 2 substituents independently selected from the group consisting of fluoro, Chloro, bromo, iodo, lower alkyl, as well as lower alkoxy. Typical substituted phenoxy lower alkyl groups are, for example, 4-fluorophenoxymethyl, 2-iodo-5-bromophenoxymethyl, 2- (2,5-dimethylphenoxyethyl, 4- (2-methoxy-4-chlorophenoxy) -1-methylbutyl or the like.

The term "substituted phenylthio-lower alkyl" refers to groups of the formula Ph'-SR ¹ -, wherein R 'is lower alkyl and Ph' is a phenyl group having 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, Bromine, iodine, lower alkyl or lower alkoxy. Typical substituted phenylthio-lower alkyl groups are, for example, 4-fluorophenyl

231058 7

thiomethyl, 2-iodo-5-bromophenylthiomethyl, 2- (2,5-dimethylphenylthio) ethyl, 4- (2-hexoxy-4-chlorophenylthio) -1-methylbutyl or the like.

The term "unsubstituted fatty acid" refers to carboxylic acids of the formula R ¹ COOH / wherein R ^{1 is} an alkyl group of 1 to 20 carbon atoms.

The term "low molecular weight primary alcohol" refers to a primary alcohol having a molecular weight within about 70, such as methanol, ethanol, or the like.

As mentioned above, the products of formula III are suitable for controlling fungi, in particular for controlling plant fungal infections (see, for example, Belgian Patent 871,668.) For example, the compounds according to the invention are used as fungicides against fungal diseases, such as downy mildew, for example Plasmopara viticola (Grapes ) and Peronospora parasitica (cabbage), late rots (for example Phytophthora infestans (tomatoes and potatoes) and plants and root rots, for example Phytophthora.

The compounds are particularly suitable fungicides because they combat certain types of fungal infections. This allows for economical utilization of the fungicides of the present invention, since they do not have to be applied to the plants until a fungal infection actually occurs. Therefore, a preventive program for applying fungicides to potential fungal infections is not required.

When used as fungicides, the compounds are applied in fungicidally effective amounts to fungi and / or their growth sites, for example vegetative and non-vegetative host sites, for example animal products. Of course, the amount used depends on

factors such as the host / type of fungus and the particular compound applied. As in the case of most pesticidal compounds, the compounds are usually not applied as such, but are generally blended with conventional biologically inert excipients or carriers normally used to facilitate the distribution of active fungicidal compounds, the formulation and mode of administration being the activity of the fungicide. The compounds can be applied in the form of granules, in the form of powdered dusts, as wettable powders, as emulsifiable concentrates, as solutions or as other known types of formulation, depending on the desired mode of administration.

Wettable powders are in the form of finely divided particles that readily disperse in water or other dispersants; These agents will normally contain from about 5 to 80% fungicide and the balance inert material, which may also include dispersants, emulsifiers and wetting agents. The powder may be applied to the soil as a dry dust, or preferably in the form of a suspension in water. Typical carriers are Fuller's earth, kaolin clays, silica and other highly absorbing wettable inorganic diluents. medium. Typical wetting agents, dispersants or emulsifiers include: the aryl and alkylaryl sulfonates and their sodium salts, alkylamidesulfonates including fatty methyltaurides, alkylarylpolyether alcohols, sulfated higher alcohols and polyvinyl alcohols, polyethylene oxides, sulfonated animal and vegetable oils, sulfonated petroleum oils, fatty acid polyhydric alcohol esters and the ethylene oxide addition products of such esters and the addition products of long chain mercaptans and ethylene oxide. Many other types of suitable surfactants are commercially available. The surfactant will be norma

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- yr -46-

L used in an amount of 1 to 15 wt .-%, based on the fungicidal agent.

Dusts are free-flowing mixtures of the active fungicide with finely divided solids such as talc, natural clays, kieselguhr, pyrophyllite, diatomaceous earth, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours and other organic and inorganic solids which act as dispersants and carriers for the Active ingredients act. These finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation contains 75% silica and 25% of the active ingredient.

Suitable liquid concentrates are the emulsifiable concentrates which are homogeneous liquids or pastes and which are readily dispersed in water or other dispersing agent and which may consist entirely of the fungicide with a liquid or solid emulsifying agent, and also include a liquid carrier such as xylene, heavy aromatic Naphthas, isophorone and other non-volatile organic solvents may be included. For application, these concentrates are dispersed in water or other liquid carrier and are usually sprayed onto the surface to be treated.

Other suitable formulations for fungicidal purposes are simple solutions of the active fungicide in a dispersant in which it is completely soluble in the desired concentration. Mention may be made of acetone, alkylated naphthalenes, JJylol and other organic solvents.

, , , Granular formulations in which the fungicide sits on relatively coarse particles are particularly suitable for aerial distribution or for penetration of crop protection covers. Pressurized sprays, typically aerosols in which the active ingredient is dispersed in a finely divided form due to evaporation of a low-boiling solvent dispersant.

- ys -

carrier, such as due to freons, may also be used. All methods for the formulation and application of the fungicides are known. The optimum weight percentages of the fungicide (active ingredient) may vary depending on how the agent is applied, further on the particular type of agent, but in general they will vary between 0.5 and 95% by weight, based on the fungicidal agent.

The fungicidal agents may be formulated and applied together with other active ingredients, for example other fungicides, insecticides, nematocides, bactericides, plant growth regulators, fertilizers, etc.

The following examples illustrate the invention without limiting it. Unless otherwise indicated, all temperatures are to ⁰ C. The terms "ambient temperature" or "room temperature" mean a temperature of about 20 to 25 ° C. The term "%" means wt% and the term "mol" stands for gramol. The term "equivalent" indicates an amount of the reagent equivalent in moles to the moles of the preceding or succeeding reactant indicated in a preparation or use example as moles or finite weight or volume. Unless otherwise stated, racemic mixtures and / or diastereomeric mixtures are used as starting materials and corresponding racemic mixtures and / or diastereomeric mixtures are obtained as products. If necessary, examples are repeated to provide sufficient quantities of starting materials for subsequent production methods and methods of use. The abbreviation E.Ä. stands for "elemental analysis, both for the calculated and found values (in% by weight).

«.J I U JU / - ^ - ιβ ·

The proton magnetic resonance spectra (PUR) are determined at 60 mliz and the signals are singlets (bs), broad singlets (bs), doublets (d), double doublets (dd), triplets (t), double triplets (dt), quartet ( q) and multiplets (m)

Ausführungsbe ispiele 1

This example illustrates step (1) of the process of the invention and the preferred hydrolysis of the salt (I) to its acid.

In carrying out this example, 15 ml of anhydrous dimethoxyethane are mixed with 1.98 g (0.022 mol) of 2-methyl-2-propanethio, 1.08 g (0.02 mol) of sodium methylate. The mixture is refluxed for 1 h, then cooled to room temperature and mixed with 4.10 g (0.02 mol) of 3- (2,6-dimethylphenylamino) -3 "-butyrolactone The resulting mixture is refluxed for 1 1/4 h After refluxing, the mixture is cooled and 20 ml of ice-water are added, the mixture is then extracted with toluene and the residual aqueous phase is refluxed, then about 0.2 g of sodium methylate is added acidified to pH 6 with glacial acetic acid and extracted with methylene chloride The methylene chloride extract is then washed three times with water, dried over magnesium sulfate and evaporated to give 2.80 g of 1-carboxy-1- (2,6-dimethylphenylamino) -3-tert .-Butylthiopropan be obtained in the form of a viscous oil.

By the same method, but using the corresponding lactone starting materials instead of 3- (2,6-dimethylphenylamino) -if-butyrolactone, the following compounds are prepared:

1-carboxy-1- (2,3,6-trimethylphenylamino) -3-tert-butylthiopropan,

1-carboxy-i- (2-methoxy-6-methylphenylamino) -3-tert-butylthiopropane and

 2.3.

1-carboxy-1-naphthylamino ~ 3 ~ tert-butylthiopropan.

Following the same procedure, but instead of preparing the thiolate in situ, the thiolate salts potassium allyl thiolate, ammonium benzylthiolate, and sodium naphthylthiolate, respectively, are reacted directly with each of the butyrolactone starting materials as mentioned above to give the corresponding thiomethylone, thiocompound, and thionaphthalene analogs of each of the above products.

Example 2

This example illustrates the second stage of the process of the invention.

To carry out this example, 1.1 g (0.0037 mol) of 1-carboxy-1- (2,6-dimethylphenylamino) -3-tert-butylthiopropane in 10 ml of methylene chloride containing 0.56 g (0.0554 g Mol) triethylamine, dissolved. The mixture is cooled to ⁰ ° C., whereupon 0.44 g (0.0041 mole) of methoxyacetyl chloride are added dropwise and the resulting mixture is stirred at 0 ^° C. for 10 minutes. The mixture is then warmed to room temperature for 30 minutes and then poured into ice-water. The methylene chloride phase is extracted, washed once with an aqueous hydrochloric acid, twice in water and then dried over magnesium sulfate and evaporated to give 1.3 g of 1-carboxy-1- / n- (2,6-dimethylphenyl) methoxyacetamidojf-3. tert.-butylthiopropane containing a small amount of 1-Methoxyacetyloxycarbonylderivat in the form of an oil. The conversion achieved in this step is approximately 95% based on the starting carboxy material.

By the same method, but using each of the products of Example 1 as the starting material, the corresponding methoxyacetamidoderoder of the formula

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(II) produced.

Following the same procedure but replacing each methoxyacetyl chloride with chloroacetyl chloride, cyclopropylcarbonyl chloride, benzoyl chloride and 2,3-epoxybutyryl chloride respectively, the corresponding chloroacetamido, cyclopropylamido, benzoylamido and 2,3-epoxybutyramido analogs of each of the compounds described above are prepared ,

Example 3

This example shows the third stage of the process according to the invention.

To carry out this example, 1.7 g (0.0046 mol) of 1-carboxy-1 N- (2,6-dimethylphenyl) -N-methoxyacetamidoj-3-tert-butylthiopropane, prepared according to Example 2, dissolved in 10 ml of anhydrous methylene chloride. The mixture is then cooled to 0 ⁰ C, whereupon 0.317 g (0.0023 mole) of phosphorus trichloride are added. The mixture is stirred at 0 ^° C. for 20 minutes and then warmed to room temperature and stirred for 1 hour at room temperature and then quenched by the addition of ice. The solution is then decanted to separate a small amount of solid precipitate that has formed. The methylene chloride phase is then removed and washed successively with water, a 5 wt .-% aqueous Natriumcarbonatlösüng, twice with water, a 1 η aqueous hydrochloric acid solution and then washed twice more with water. The washed mixture is then dried over magnesium sulfate and evaporated to give 1.0 g of 3- (N-methoxyacetyl-N-2,6-dimethylphenylamino) -tf-butyrothiolactone as an oil. The oil is then recrystallized from isopropyl alcohol. The infrared spectrum as well as the proton magnetic resonance spectrum of the crystalline product are with the spectra of a comparative sample

2.310.58, 7

of 3- (N-methoxyacetyl-N-2> 6-dimethylphenylamino) -J'-butyrolactone identical.

Following the same procedure, but using the corresponding products of Example 2 as starting materials, the corresponding butyrothiolactone derivatives are prepared.

Example 3A

This example illustrates the third stage of the process of the invention using a cyclization agent other than that used in Example 3.

To carry out this example, a solution containing 0.24 g of sulfuric acid, 4 ml of toluene and 6 ml of acetic acid is added to 2.35 mmol of 1-carboxy-1- / ν- (2,6-dimethylphenyl) -N-methoxyacetamide / 3-tert-butylthiopropane. The mixture is then heated to reflux (about 11O ⁰ C) for 2 hours and then cooled and washed twice with 10 ml of water. (a small amount of methylene chloride is added to prevent precipitation of solids during washing). The washed mixture is then evaporated to dryness at 50 ^° C. to give 3.65 g of 3- (N-methoxy-acetyl-N-2,6-dimethylphenylamino) -i-butyrothiolactone in the form of a solid The methylene chloride extract is evaporated to dryness to give an additional 0.27 g of 3- (N-methoxyacetyl-N-2,6-dimethylphenylamino) -fu-butyrothiolactone as a solid.

Following the same procedure, but using the corresponding products of Example 2 as starting materials; the corresponding butyrothiolactone derivatives are prepared.

2310 58 7

Examples 4 to 6 show the process according to the invention, in the implementation of which the salt (I) is acylated directly without prior conversion into the acid.

To carry out this example, 9.5 g (0.1 mol) of 2-methyl-2-propanethiol are added to a stirred slurry containing 6 g of sodium methylate (0.1 mol) in 70 ml of anhydrous 1,2-dimethoxyethane at room temperature. The resulting mixture is stirred at room temperature for about 30 minutes (resulting in the formation of sodium 2-methyl-2-propanethiolate) followed by 20.5 g (0.1 mol) of 3- (2,6-dimethylphenylamino) - ^ f-butyrolactone can be added. The mixture is then heated to reflux until the slurry clears (after about 1 hour). The solution is evaporated to remove solvent and by-product methanol to give sodium 1- (2,6-dimethylphenylamino) -1- (2-tert-butylthioethyl) acetate (I) as a residue.

Following the same procedure, but with the corresponding 3-aryl or substituted arylamino ^. Butyrolactone starting materials are used, the following compounds are prepared in each case: sodium 1- (phenylamino) -1- (2-tert-butylthioethyl) acetate,

Sodium 1- (4-fluorophenylamino) -1- (2-tert-butylthioethyl) -acetate,

Sodium 1- (2-iodophenylamino) -1- (2-tert-butylthioethyl) -acetate,

Sodium 1- (2,6-dichlorophenylamino) -1- (2-tert-butylthioethyl) -acetate,

Sodium 1- (2-methoxyphenylamino) -1- (2-tert-butylthioethyl) acetate,

Sodium 1- (2-methyl-4-pentyl-phenylamino) -1- (2-tert-butylthioethyl) -acetate,

2310 58 7

Sodium 1- (2,6-dibromopheny! Amino) -1- (2-tert-butylthioethyl) -acetate, as well as

Sodium 1 - acetate -1- (2-tert-butylthioethyl) - (methyl-S-chloro-phenylamino ^).

By the same method but substituting potassium hex-4-enyl thiolate, calcium di (methyl thiolate) and ammonium benzyl thiolate for the sodium 2-methyl-2-propanethiolate prepared in situ, the corresponding analogous salts of each of the above products are prepared.

Example 5 .

To carry out this example, the sodium 1- (2,6-dimethylphenylamino) -1- (2-tert-butylthioethyl) acetate (I) residue of Example 4 is redissolved in 250 ml of dimethoxyethane and heated to reflux. 7.5 g (0.1 mole) of N, N-dimethylformamide are then added, followed by the addition of 9.5 g (0.1 mole) of acryloyl chloride. At this point, the solution turns light brown. The mixture is cooled to room temperature, whereupon a further 7.5 g (0.1 mol) of Ν, Ν-dimethylformamide are added. This is followed by the addition of another 9.5 g (0.1 mol) of acryloyl chloride. The mixture is then refluxed for 1½ hours and then evaporated under vacuum to remove the solvent. The residue is slurried with diethyl ether, filtered through diatomaceous earth and evaporated to give acrylic acid 1- (N- (2,6-dimethylphenyl) -N-acryloylamino-2- (2-tert-butylthioethyl) -acetic anhydride in the form of a residue - fäiit .. "'-.' . '''''*','/', .. ^'';; '·...' -.. '' \\ ^'; ·;

Following the same procedure, using the corresponding products of Example 4 as starting materials, the following compounds are each prepared:

2310 58 7

acrylic acid 1 - (N-phenyl-N-acryloylamino) -1- (2-tert-butylthioethyl) -acetic anhydride,

acrylic acid 1-χΝ- (4-fluorophenyl) -N-acryloylamino-7-2-tert-butylthioethylacetic anhydride,

acrylic acid 1 - / N- (2,6-dichlorophenyl) -N-acryloylamino_7-2-tert-butylthioethylosuccinic acid cancans, acrylic acid 1- / Ν- (2-mothoxyphcnyl) -N-acryloylaminoJ-2-tert-butylthioethylacetic anhydride, acrylic acid 1 - / n- (2-methyl-4-pontylphenyl) -N-acryloylaminoJ-2-tert-butylthioethylacetic anhydride, acrylic acid 1- / N- (2,6-dibromophenyl) -N-acryloylamine-2-tert-butylthioethylacetic anhydride and acrylic acid 1- / v- (2-methyl-3-chlorophenyl) -N-acryloylaminocyc-2-tert-butylthioethylacetic anhydride.

By the same procedure but substituting acetyl chloride, dichloroacetyl chloride, hydroxyacetyl chloride, methoxyacetyl chloride, methylthioacetyl chloride, phenylthioacetyl chloride, phenoxyacetyl chloride, 2,6-dimethylphenylacetyl chloride, 4-ethoxyphenylacetyl chloride and 2,3-epoxybutyryl chloride, respectively, instead of acryloyl chloride, the corresponding diacyl derivatives become each of the above-identified compounds, for example, acetic acid 1- (n-2,6-dimethylphenyl) acetamido 2-tert-butylthioethylacetic anhydride. dichloroacetic acid 1- (N-phenyl-dichloroacetamido) -2-tert-butylthioethylacetic anhydride,

Hydroxyacetic acid 1- (n-4-fluorophenyl) -hydroxyacetamido-2-tert-butylthioethylacetic anhydride, methoxyacetic acid (1-, 2- (2,6-dimethylphenyl) methoxyacetamido-2-tert.-butylthioethylacetic anhydride, methylthioacetic acid (1-N) (2,6-dichlorophenyl) methylthioacetamido J-2-tert-butylthioethylacetic anhydride, phenylthioacetic acid 1- (n-2-methoxyphenyl) phenylthioacetamido-2-tert-butylthioethylacetic anhydride, phenoxyacetic acid 1- (n-2-methyl) -acetic acid -pentylphenyl) phenoxyacetamido J-2-tert-butylthioethylacetic anhydride, (2,6-dimethylphenyl) acetic acid 1- ^ N- (2,6-dibromophenyl) -

2310 58 7

(2,6-dimethylphenyi) acetarrido-2-tert-butylthioethylacetic anhydride, «

(4-ethoxyphenyl) acetic acid 1- / v- (2-methyl-3-chlorophenyl) - (4-ethoxyphenyl) acetamidoj-2-tert-butylthioethylacetic anhydride,

2,3-epoxybutyric acid 1- / n- (2,6-dimethylphenyl) -2,3-epoxybutyramide J7-2-tert-butylthioacetic acid anhydride etc.

Example 6 .

To carry out this example is the 1-acrylic acid 1- / N- (2, 6-Dimethylpheny1) -N-acryloylaminoJ-2-tert-butylthioethylessigsäureanhydridrest of Example 5 with 200 ml of dimethoxyethane are mixed, after which 42 g (0.3 mol) Phosphorus chloride are added slowly. The resulting mixture is cooled to about 8 ° C and then stirred at room temperature overnight (about 12 hours). Thin-layer chromatographic analysis of a small sample of this material shows the presence of some unreacted starting materials (ie butylthiopropane derivatives) and two other products. The reaction mixture is then heated to reflux for 24 hours and then evaporated to remove the solvent. The residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate to neutralize the acidic components and then washed with water and dried over magnesium sulfate. The methylene chloride is then removed by evaporation to give an oily residue. The oily residue is then chromatographed over 250 g of silica gel and then eluted with petroleum ether; 95% petroleum ether and ethyl ether; 90% petroleum ether and ethyl ether; 75% petroleum ether and ethyl ether. The silica gel column is then further eluted with 50% petroleum ether and ethyl ether to give about 3 g of 3- (N-acryloyl-N-2,6-phenylamino) -2f-butyrothiolactone.

Following the same procedure, the products of Example 5 are each converted to the corresponding δ-butyrothiolactone derivatives, for example in:

3- (N-Acryloyl-N-2,6-dichlorophenylamino) -tf-butyrothiolactone, 3- / N-AcTylyI-N- (2-methyl-3-chlorophenyl) -amine] -o-butyrothiolactone,

3- (N-Dichloroacetyl-N-phenylamino) - ^ "- butyrothiolactone, 3- (N-methoxyacetyl-N-2 ', 6'-dimethylphenyl-amino) - (f-butyrothiolactone,

3- (N-phenylthioacetyl-N-2'-methoxyphenylamino) -f-butyrothiolactone,

3- / N- (2,6-dimethylphenyl) acetylJ-N- (2,6-dibromophenyl) -aminoJ-Tf butyrothiolacton,

3- / N- (2,3-epoxybutyryl) -N- (2, 6-dimethylphenyl) butyrothiolactone etc.

Example 7

To carry out this example, the methods of Examples 2 and 5 are repeated except that the corresponding acyl bromides are used instead of the acyl chloride. Samples of the resulting products of formula II are then each converted to the corresponding compounds of formula III by applying the method of example 3 and the methods of example 3A.

Example 8

This example illustrates another method of the present invention.

Ä. A solution of 11.89 g of 3- (N-2,6-dimethylphenylamino) -O-butyrolactone in dimethoxyethane is added to 6.5 g of sodium tert -butylmercaptide

2310 58 7

Boiled reflux and then stripped. The residue is dissolved in water, acidified with hydrochloric acid and extracted with methylene chloride. The organic phase is collected, dried (MgSO ₄ ) and stripped to give 15.2 g of a viscous oil (the IR spectrum shows the presence of -CO ₃ H).

B. A 5 g portion of the oil is in 10 ml (15.7 g) of phosphorus trichloride at 7, always stirred temperature for 2 days, The excess of phosphorus trichloride is stripped off at 6O ⁰ C and the residue dissolved in methylene chloride, washed with water and dried. The residue is purified on a silica gel column to obtain 1.31 g of 3 ⁱ - (N-2,6-dimethylphenylamino-y-butyrothiolacton (yield 34.8%) "·. '.'

C. The product of Step B is then acylated according to the method described in Example 2 to give 3- (N-methoxyacetyl-N-2,6-dimethylphenyl-amino) -Jf-butyrothio

lactone is obtained.

Claims (27)

wherein Ar is aryl or substituted aryl having 1 to 4 substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, lower alkyl or lower alkoxy, and R is lower alkyl, lower alkoxy, cycloalkyl of 3 to 6 carbon atoms , Lower-alkenyl, lower-alkenyl, lower-alkenyloxy, hydroxymethyl, haloalkyl having 1 to 3 halogen substituents and 1 to 6 carbon atoms, lower alkoxyalkyl, lower alkylthioalkyl, phenylthio-lower alkyl, phenoxy-lower alkyl, phenylthio-lower alkyl or substituted phenoxy-lower alkyl having 1 or 2 ring substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, lower alkyl and lower alkoxy, and 1 '
where R is selected from the same group as the substituents R. 1 2
in which Ar, R and R have the meanings given in claim 1, M is a cation, R is lower alkyl, lower alkenyl or aryl-lower alkyl, and R is H or the radical Il 1 I -CR 1
wherein R has the meaning given above and X is chlorine or bromine, in an inert organic solvent under reactive conditions at temperatures between about 0 and 120 ⁰ C to obtain the corresponding acylated product of the formulas 0 o CR ¹ R ² , CR ¹ R ² / I / I Ar - N-CH-CH ₂ -CH-SR; Ar - N-CH-CH ₂ -CH-SR C = O C = O OH (Ha) 0 Il '. , ^: . O-CR ¹ (Hb) 12 wherein Ar, R, R and R have the meanings indicated and R is Hiedrigalkyl contacted, or .. (d) the acylated product of step (c) with a cyclizing agent selected from the group of compounds 231058 7 which cause an esterification of a saturated fatty acid with a low molecular weight primary alcohol / is contacted in an inert organic solvent under reactive conditions to obtain the corresponding _% / compound of formula III. 2. The method according to item 1, characterized in that for carrying out the process variant A), the compound of formula (A) consists of 3- (2,6-dimethylphenylamino) -ir-butyrolactone. '' 2 '''' in which Ar and R have the meanings given above, with a thiolate salt of the formula wherein M is an alkali metal cation and R is lower alkyl, lower alkenyl or aryl-lower alkyl is, in an inert organic liquid carrier under reactive conditions at temperatures between about 20 and 200 ⁰ C to obtain the corresponding compound of formula 58 7 .- yf- 3k- R ² HI Ar - N - CH - CH ₉ --CH - SR I.
C = O I (I) OM wherein Ar, MR and R have the meanings given above, is contacted, (b) the compound of formula I is contacted with an acid under reactive conditions to obtain the corresponding i-arylamino-i-carboxy-3-thiopropane, (c) the 1-arylamino-i-carboxy-S-thiopropane with an acyl halide of the formula 0
RCX,   '' 2 '·' .-. , wherein Ar and R have the meanings given above, with a thiolate salt of the formula wherein M is an alkali metal cation and R is lower alkyl, lower alkenyl or aryl-lower alkyl is, in an inert organic liquid carrier under reactive conditions at temperatures between about 20 and 200 ⁰ C to obtain the corresponding compound of formula Ar-N-CH-CH ₂ -CH-SR '': '"''.' , C »o. '.-.;' Ν - ^: ':.'' , '. '.- .. wherein Ar, R and R have the meanings given above, is contacted, (b) the compound of formula (I) with an acyl halide of the formula . '..'.;::: "· '.. .r'-cx:;... ·... 231058 wherein R has the meaning given above and X is chlorine or bromine, in an inert organic solvent under reactive conditions at temperatures between about 0 and 120 ^° C to obtain the corresponding acylated product of the formula O O It Il , CR ¹ R ² CR ¹ R ² / ι / ι Ar - N-CH-CH ₉ -CH-SR; Ar - N-CH-CH ₉ -CH-SR II C = O C = O OH (Ha) 0 Il O-CR ¹ (Hb) 12 worm Ar, R, R and R have the meanings given above and R is lower alkyl, is contacted, or (c) the acylated product of step (b) with a cyclizing condensing agent selected from the group of compounds which esterify a saturated fatty acid with a lower molecular weight primary alcohol in an inert organic solvent under reactive conditions to obtain the corresponding Compound of formula III is contacted j or (a) an arylaminolactone of the formula H Ar -N Young Women (A) 2
R is hydrogen, chloro, bromo, lower alkyl, phenyl, substituted phenyl having one or two ring substituents independently selected from the group consisting of fluoro, chloro, bromo or lower alkyl, characterized in that 3. The method according to item 1, characterized in that the thiolate salt used to carry out process variant A) is an alkali metal thiolate. 4. The method according to item 1, characterized in that for carrying out the process variant A) the thiolate salt consists of sodium 2-methyl-2-propanethiolate. 5. The method according to item 1, characterized in that for carrying out process variant A), the thiolate salt of the formula . ' '' '·: "'^:- '' '' ο.:. · '. v ';. ·. '; , .-^;, , '. "'.' ". .. ·'  .. '". ^{:   ;}   CR ¹ R ²        'ι .. ... .: '. · · '. . ; Ar-N-CH-CH ₉ CH-SR '.'. '.': .. ''' ^{c = 0} ''-'.:'''.'' ^: '.;' ^: OR ³ (II) 2310 58 6. The method according to item 1, characterized in that for carrying out the process variant A) the stage (b)
at temperatures between about 0 and 12O ⁰ C is performed. -6.AUG.1982 * Ü274O3 2310 58 7 a): ;; .-. ..:;. ^·: Ν -; ν .'s ^: xχ ",," ^: - ^: -.ο:>:: .-,. . ^·: ' (a) the corresponding aryl-amino-γ-butyrolactone of the formula .:. · '.-.: - ^; ''. '''' :. : Ar - N. (A) wherein Ar and R have the meanings given above, is reacted with a thiolate salt under reactive conditions to obtain the corresponding 1- (ar-amino) -3-thiopropane-1-carboxylate salt, (b) the 1- (ar-amino) -S-thiopropane-i-carboxylate salt with an acyl halide of the formula ^::: "..;"'/.'·''. · '·;^'O'::: / /. "'. ^: '... wherein R has the meaning given above and X is chlorine or bromine, is contacted, (c) the N-acylamino product of step (b) with a cyclization agent which is an esterification of a saturated fatty acid on contact with a primary fatty acid
Low molecular weight alcohol causes under
reactive conditions for obtaining the corresponding compound of formula III is contacted, or optionally the step (c) before the step (b) to obtain the corresponding thiolactone intermediate
carried out and the thiolactone intermediate according to
aeyliert the step (b) for obtaining the compound of formula III, or 231058 7 B) (a) that corresponding arylamine »- 7-butyrolactone of the formula H Ar-N R ² (A) wherein Ar and R have the meanings given above, is reacted with a thiolate salt under reactive conditions to obtain the corresponding 1- (arylamino) -3-thiopropane-1-carboxylate salt, (b) contacting the carboxylate salt with an acid under reactive conditions to obtain the corresponding 1- (aryl, amino) -i-carboxy-3-thiopropane, (c) the 1- (arylamino) -1-carboxy-3-thiopropane with an acyl halide of the formula ι »
R CX in which R has the meaning given above and X is chlorine or bromine, and (d) contacting the N-acylamino product of step (c) with a cyclizing agent capable of converting carboxylic acids or esters to acid halides under reactive conditions to obtain the corresponding compound of formula H-I, or 23VO58 7 (A) 7. The method according to item 1, characterized in that for carrying out the process variant A) the stage (a) carried out in an inert organic liquid
becomes. 8. The method according to item 1, characterized in that for carrying out the process variant A), the step (b) is carried out in an inert organic solvent. 9. The method according to item 1, characterized in that for carrying out the process variant A), the step (c) is carried out in an inert organic solvent. 10. The method according to item 1, characterized in that for carrying out the process variant A) the 1- (arylamino) -3-thiopropanecarboxylate salt with about 2 to 2.2 moles of the acyl halide per mole of the
Salt in the step (b) is contacted. L οι υ ^ u # 11. The method according to item 1, characterized in that for carrying out the process variant B), the compound of the formula (A) consists of 3- (2,6-dimethylphenylamino) -butyrolactone. 12. The method according to item 1, characterized in that for carrying out the process variant B) that Ar is 2,6-Dime thy I-phenyl. 13. The method according to item 1, characterized in that for carrying out process variant B), the thiolate salt used is an alkali metal thiolate. 14. The method according to item 1, characterized in that for carrying out process variant B), the thiolate salt used consists of sodium 2-methyl-2-propanethiolate. 15. The method according to item 1, characterized in that carried out for carrying out the process variant B), the step (c) at temperatures between about O and 12O ⁰ C. ./becomes..''' ·..·. ''';' . '/V':.- 16. The method according to item 1, characterized gekennzeichn, et, that for carrying out the process variant B), the step (a) is carried out in an inert organic liquid. 17. The method according to item 1, characterized in that for carrying out the process variant B), the step (c) is carried out in an inert organic solvent. 18. The method according to item 1, characterized in that for carrying out the process variant B), the step (d) is carried out in an inert organic solvent. 19. The method according to item 1, characterized in that
in step (c) the 1- (arylamino) -i-carboxy-3-thiopropane with about 1 to 1.1 moles of the acyl halide
per mole of 1- (arylamino) -carboxy-3-thiopropane is treated. 58 7- 20. The method according to item 1, characterized in that for carrying out the process variant C), the inert organic liquid of step (a) is selected from the group consisting of 1,2-dimethoxyethane, diglyme and mixtures thereof, and the inert used organic solvents of steps (b) and (c) are independently selected from the group consisting of glacial acetic acid, dichloromethane, 1,2-dichloroethane, toluene or mixtures thereof. .21 · Method according to item 1, characterized in that for carrying out the method variant D) in the stage (a) used inert organic Liquid selected from the group consisting of 1,2-dimethoxyethane, diglyme and mixtures thereof, and the inert organic solvents of steps (b) and (c) are independently selected from the group consisting of glacial acetic acid, dichloromethane, 1 , 2-dichloroethane, toluene and mixtures thereof. 22. The method according to item 1, characterized in that for Implementation of process variant D) the cyclizing condensation agent used ^: is selected from the group consisting of phosphorus trichloride and mixtures of glacial acetic acid containing a minor amount of sulfuric acid. 23. The method according to item 1, characterized in that for carrying out the process variant D) in the step (a) used inert organic liquid consists of 1,2-dimethoxyethane and in the steps (b) and (c) used inert organic Each solvent consist of methylene chloride. 58 7 - 31 ". 24. The method according to item 1, characterized in that for · ':.: ":': 2 Implementation of the process variant D) R is hydrogen. 25. The method according to item 1, characterized in that for carrying out the method variant D) the starting material of the formula A used consists of (2,6-dimethylphenylamino) -7-butyrothiolactone and the acyl halide used consists of methoxyacetyl chloride, and the product of the formula III of the formula equivalent. 26. The method according to item 1, characterized in that for carrying out the process variant D) the used
Thiolate salt is an alkali metal thiolate. 27. The method according to item 1, characterized in that for carrying out the method variant D) used
Thiolate salt consists of sodium 2-methyl-2-propanethiolate.