NL8103024A - PROCESS FOR PREPARING 3- (N-ARYL-N-ACYLAMINO) -) / - BUTYROTHIOLACTONES. - Google Patents

Description

* Λ * ι 7> Ν.0. 30,202

Process for preparing 3 "(N-aryl-N-acylamino) -y-butyrothio-lac. _________________________________________

The invention relates to a method and intermediates for the preparation of 3- (N-aryl-N-acylamino) - / - butythiolactones.

3_ (N-aryl-N-acylamino) - / - butyrotiolactones are known compounds with a fungicidal activity and are described in Belgian patent 871,668. According to the Belgian patent, the compounds are prepared by amination (anilination) of a 3-balogen - / - butyrotiolactone followed by acylation with the required acyl halide.

10 In patent application 81.

a method is described for preparing such compounds by cleaving the corresponding N-aryl-N-acyl-aminolactones with a tbiolate salt followed by treatment of the obtained (N-aryl-N-acylamino) -carboxythioalkane product with phosphorus tricbloride to close the ring.

A discussion of the preparation of certain unsubstituted thiolactones is found in an article by Truce et al. In the Journal of Organic Chemistry, Vol. 28, p. 964 (April 1963)

The invention provides an improved process for preparing high yields of 3- (N-aryl-N-acylamino) - / - tbio-butyrolactones and intermediates formed thereby.

The process of the invention comprises the following steps: (a) contacting a 3- (arylamino or substituted arylamino) - / - butyrolactone or 5-substituted derivative thereof with a tbiolate salt under reactive conditions to form the corresponding a- (arylamino or substituted arylamino) -a-thioalkane-carboxylic acid salt and acidification of the salt to obtain the corresponding carboxylic acid, and (b) contacting under reactive conditions of the product of step (a) with a acyl halide to form the corresponding acylamino derivative, and (c) contacting the product of step (b) with a cyclizing agent which will effect esterification of a saturated fatty acid with a low molecular weight primary alcohol. formation of the corresponding 3- (N-aryl or substituted aryl-N-acylamino) / butyrothiolactone or 5-substituted derivative thereof. _________________________________________ 8103024 * 5 2

It is also possible to reverse the order of steps (b) and (c) and thus first cycle the intermediate of step (a), followed by acylation.

In one embodiment, the method of the invention can suitably be schematically represented by the overall reaction scheme as indicated in the accompanying Figure 1, wherein Ar represents an aryl or substituted aryl group having 1 to k substituents, which substituents are independent of each other fluorine, chlorine, bromine, iodine atoms, alkyl and / or alkoxy groups, R represents an alkyl group (preferably tert-butyl group), alkenyl group (preferably allyl group) or aralkyl group (preferably benzyl group), R an alkyl or alkoxy group, cycloalkyl group of 3 to 6 carbon atoms (preferably cyclopropyl group), epoxyalkyl group of 2 to 6 carbon atoms and one or two epoxy groups, alkenyl or alkenyloxy group, hydroxyalkyl group (preferably hydroxymethyl group), haloalkyl group having 1 to 3 halogen substituents and 1 to 6 carbon atoms, alkoxyalkyl or alkylthioalkyl group, phenylthioalkyl group (preferably phenylthiomethyl group), phenoxyalkyl group (b (preferably phenoxymethyl group), substituted phenylthioalkyl group (preferably substituted phenylthiomethyl group) or substituted phenoxyalkyl group (preferably substituted phenoxymethyl group) with one or two ring substituents, which ring substituents independently of each other are fluorine, chlorine, bromine, iodine atoms, alkyl and / or alkoxy-25 groups, and R represents a hydrogen, chlorine, bromine, alkyl, phenyl or substituted phenyl group having one or two substituents, which substituents independently of each other are fluorine, 3 chlorine , bromine atoms and / or alkyl groups, R represents a hydrogen 1 1 1 1 atom or a radical, where R represents the

-CR

30 has meaning, and M represents an inorganic cation, preferably an alkali metal cation, and m corresponds to its valence, and X represents a chlorine or bromine atom.

Step Ca) of the process, as illustrated by the reaction scheme of Fig. 1, may conveniently be carried out by the appropriate compound of formula 1 having the desired substituents Ar and R under reactive conditions. xn contact with the thiolate of the formula II, preferably in a suitable organic solvent. _________ Suitably, this conversion is initiated in the course of

jC6336lC

81 03 0 2 4

^ * A

spring 1 to 8 hours, preferably about 1 to k hours, conducted at temperatures within the range of about 20 to 200 ° C, preferably 50 to 80 ° C. Suitably, about 1 to 1.5 moles are preferably about 1 to 1.25 moles of the compound of the formula II (based on the thiolate content) per mole of the compound of the formula I are used.

When an organic solvent is used * the solvent alone is generally a solvent for the reactant of the formula 1 * Suitable inert organic solvents which can be used are, for example, dimethoxyethane, toluene, tetrahydrofuran, dimethylformamide and the like and compatible mixtures thereof * Dimethoxyethane is preferably used as a solvent. Suitably, a liquid environmental ratio of about 1 to 5 moles of the reactant of the formula 1 per liter of the solvent is used.

Generally, best results are achieved by conducting the reaction at temperatures within the range of about -50 to 80 ° C using 1 to 1.10 moles of the compound of formula II per mole of the compound having formula 1 in dimethoxyethane.

Suitable thiolates of the formula II which can be used are, for example, alkali metal thiolates, for example sodium 2-methyl-2-propanethiolate, potassium 2-methyl-2-propananthio-. late; alkaline earth metal thiolates, for example calcium bis (alkyl thiolate); ammonium thiolates; quaternary amine thiolates, for example, tetramethylammonium benzylthiolate and the like. In terms of yields when alkyl mercaptides are used, tertiary alkyl mercaptides are preferred over secondary and primary alkyl mercaptides, and secondary alkyl mercaptides are preferred over primary alkyl mercaptides. Generally, the best results are achieved using sodium 2-methyl-2-propanethiolate. In a preferred embodiment, the thiolate salt is prepared in situ by reacting the appropriate RSH mercaptan with an alkali metal alkoxide (eg sodium methanolate) .

The compounds of the formula I are known compounds and can be prepared according to known methods, for example by reacting the respective arylamine or substituted aryl amine with the relevant 3-chloro or 3-bromo-butyrolactone, as described, for example, in the Belgian patent 871 * 668, 40 81 03 02 4 * k

U.S. Patent 3,933,886 or U.S. Patent 1,553,322.

The product of step (a) according to the reaction scheme of Fig. 1 is the respective M salt of the acid of the formula 3. Before carrying out the second step of the process, it is particularly preferred that all unreacted remove the compound of the formula I from the reaction product. This can be conveniently done by extraction, because the compound of the formula 1 is generally water-insoluble, while the compound of the formula 3 is water-soluble.

The salt of the formula III can then be reacted with the acyl chloride or bromide of the formula <tf> according to step (b) of the reaction scheme of Figure 1 or is preferably hydrolyzed first to the acid of the formula III by treatment with a weak acid, such as acetic acid. If desired, the hydrolysis can generally be carried out in situ. The treatment with acid provides an economic advantage and in some cases also gives rise to a purer conversion product of the acylation than is obtained by direct acylation of the salt of the formula III.

An economic advantage is provided because the acid (eg acetic acid) is considerably less expensive than the acyl halide of the formula. If the salt of the formula 3 is directly acylated, 2 moles of the acyl halide are stoichiometric per mole of the salt of the formula 3 required. By first hydrolyzing the salt of the formula III, one mole of this acyl halide is replaced by a mole of the less expensive acid.

In the second step of the process, as illustrated by the reaction scheme of Fig. 1, the salt of formula 3 or the acid thereof is contacted under reactive conditions with the appropriate acyl chloride of formula 4, preferably in an inert organic solvent and optionally in the presence of an organic base as an acid binding agent. It has been found that at this stage of the process the product of formula III is obtained in very high yields. The acylated product of formula (5) is further more satisfactory in the cyclization reaction (step c according to the reaction scheme of Fig. 1) than the corresponding secondary amine, which is probably due to the protection of the free NH group by an acyl group. The product is generally a mixture of the α-carboxylic acid and its anhydride (ie 81 03 0 2 4 / * 5 \

O

2 II 1 I

Έτ represents -CR) depending on the relative molar ratio of the reactants

This reaction is usually carried out over a period of about 1 to 8 hours at a temperature within the range of 0 to 120 ° C, if a base is used as an acid binding agent. Preferably the lower temperatures are used, ie temperatures of 0 to 25 ° C. If a base is not used as an acid binding agent, higher temperatures are used, usually temperatures of 80 to 120 ° C, to remove the hydrogen chloride formed as a by-product from the reaction medium as gas. Generally, about 2 to 2 * 5 moles, preferably about 2 to 2.2 moles of acyl chloride of the formula k are used per mole of the reactant of the formula 3 (salt) and about half of this amount of acid halide, if the acid of formula 3 is used (i.e. about 1.0 to 1.5 moles, preferably about 1.0 to 1.10 moles of acid chloride per mole of acid of formula 3)

Suitable inert organic solvents which can be used are, for example, chlorinated hydrocarbons, eg dichloromethane, ethyl acetate, dimethoxymethane, benzene, dioxane, tetrahydrofuran and the like, and compatible mixtures thereof. If the reaction is carried out in the presence of an organic base as an acid binding agent to react with the hydrogen chloride formed as a by-product are suitable bases which can be used as acid binding agent, for example triethylamine, pyridine, 2,6-lutidine, sodium carbonate and the like;

The acyl chlorides and bromides of the formula ij. are known compounds and can be prepared by known methods or obvious modifications thereof (eg replacement of suitable substrates, solvents, etc.) »In general, it is preferred to use acyl chlorides ·

The final step (c) of the reaction scheme of Fig. 1 is preferably carried out by contacting the compound of the formula 5 under reactive conditions with a suitable cyclizing agent, preferably in a suitable inert organic solvent.

This conversion is suitably carried out over a period of about Λ / k hour to 2 hours, preferably about 1 / if to 1 hour, at a temperature within the range of 0 ° C to the temperature »at which reflux occurs» preferably above about 5 ° C. In general, about 1 to 5 moles, preferably about 2 to 2.5 moles, of the reactant 5 of the formula 5 are used per mole of The cyclizing agent used · Optimal temperatures and proportions of the cyclizing agent will vary depending on the particular cyclizing agent used, for example, if sulfuric acid is used as a cyclizing agent, "preferably a relatively small amount will be used · If, for example, phosphorus trichloride is used as cyclizing agent is used, it is preferable to use about 2 to 2.5 moles of the reactant of formula 5 per mole of phosphorus trichloride ·

Since water is formed as a by-product, it is also preferable to carry out the reaction under conditions whereby water is removed from the reaction system, for example by distillation or by using cyclizing reagents, etc., which bind water.

Suitable inert organic solvents which can be used are, for example, chlorinated hydrocarbons, for example dichloromethane, ethyl acetate, benzene, dialkyl glycols, for example 1,2-dimethoxyethane, and the like and compatible mixtures thereof. Usually, a solvent ratio of about 0.5 to 3 mol of the reactant of the formula 5 per 25 liters of solvent used

A very large number of cyclizing agents can be used. These reagents can be defined as reagents which will effect the esterification of a saturated fatty acid when the acid is in contact with a low molecular weight primary 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; tetrachloroacetic acid p-toluenesulfonic acid; monoalkyl dihydrogen phosphites, for example, 35 decyl dihydrogen phosphite; boron trifluoride etherate; sulfonic acid type ion exchange resins; phosphorus trichloride, phosphorus tribromide, phosphoric acid, thionyl chloride, phosphorus pentachloride, sulfuric acid, phosgene, oxalyl chloride, carboxylic acids and the like and compatible mixtures thereof.

hO— Very good results are obtained by transposing the 81 0 3 0 2 4

rJ'jö936LC

7% by weight using about 2 to 2 * 5 nol of the reactant of formula 5 per mole of phosphorus trichloride in dichloromethane at temperatures within the range of about 5 to 15 ° C.

Good results are also obtained using acetic acid with a small amount of sulfuric acid as a cyclizing agent when the reaction is carried out at the temperature at which the reaction mixture is refluxed.

Also, the order of the acylation and cyclization steps are reversed. This can be explained schematically with reference to the overall reaction scheme of Fig. 2, in which Ar and R have the above meanings.

Steps (b ') and (c *) can be performed in the same way as described above with respect to steps (c) and (b), respectively. As in the case of step (b), it should prefer to use the acid form of the compound of formula 3 as starting material for the step (b1) and not the salt form thereof ·

In any of the above steps of the process, * unless otherwise stated *, it is preferable to separate the respective products of formulas 3 and 5 as well as 7 before carrying out the next step of the process. apart from the hydrolysis of the salt of the formula III to its acid, it is generally preferred to carry out the process under substantially anhydrous conditions. The respective products of formulas 3, 5, 7 and 6 can be separated from the respective reaction mixtures by any suitable purification method * such as, for example, evaporation * extraction * crystallization * chromatography * distillation and the like. Specific examples of suitable separation and purification methods are described. illustrated by the examples below, it being understood, however, that other suitable methods may also be used ·

It will also be appreciated * that to the extent that specific reaction conditions (eg, temperatures, molar ratios, reaction times, etc.) are indicated, conditions both below and above these ranges may also be used, although generally less suitably or at less economically. Optimal reaction conditions (e.g., temperatures, solvents, reaction times) may vary for certain kO reactants, concentrations, etc. used but 8103024. 8 * can not be hand. of routine trials are determined

As used in the description of the invention, the following terms have the following meanings unless otherwise clearly stated. The term "halogen" denotes the group of fluorine, chlorine, bromine and iodine.

The term "alkyl group" denotes both straight and branched alkyl groups having a total of 1 to 6 carbon atoms and thus includes primary, secondary and tertiary alkyl groups. Typical examples of the alkyl groups are, for example, methyl, ethyl, n.propyl, isopropyl, n.butyl, tert.butyl, n.hexyl groups and the like.

The term "alkoxy group" denotes the residue Rf0-, wherein R 'represents an alkyl group, so that the alkoxy groups are also limited to alkoxy groups of 1 to 6 carbon atoms, for example, metho-15-ethyl ethoxy, tert-butoxy, hexoxy groups and of such.

The term "epoxyalkyl" denotes epoxyalkyl groups of 2 to 6 carbon atoms and one or two epoxy groups. Such groups are, for example, the 1,2-epoxypropyl- (i.e. / 0 \ C12-dH-CH-), 2jA-epoxy-pentyl- (i.e. V-methyloxetanylmethyl-j CH2 -CH-C ^ -CH -CH ^), 1,2 / f, 5- <3iepoxyhexyl- (i.e. -C ^ 1 ~ 0Η-) groups and the like.

The term "hydroxyalkyl group" denotes a group of the formula HOR'- wherein Rr represents an alkyl group such as, for example, hydroxymethyl, 3-hydroxypatyl, 2-hydroxyethyl and the like.

The term "alkoxyalkyl group" denotes the radical of the formula Η · ΟΗ "-, wherein R'0 represents an alkoxy group and R" represents the alkylsubstituted alkylsole substituted above by the alkoxy group.

* The term "alkylthioalkyl group" denotes a radical of the formula R'SR "- wherein R" and R "independently have the meanings mentioned. Typical examples of the alkylthioalkyl groups are, for example, methylthiomethyl and 4-tert-butylthio-35hexy group and

The term "alkenyl group" denotes unsaturated double bond alkyl groups and includes both straight and branched chain alkenyl groups having 2 to 6 carbon atoms. Typical examples of the alkenyl groups are ally, but-3-enyl, 2-methylpent-if-enyl group 81 03 0 2 4 9 pea and the like.

The term "alkenyloxy group" denotes groups of the formula R ^ O— wherein ΐΡ represents an alkenyl group, as defined above.

The term "alkenyloxyalkyl group" denotes groups of the formula R ^ OR'-, wherein R ^ represents an alkenyl group and R 'represents the alkyl group substituted by the alkenyl oxy group, as defined above. Typical examples of the alkenyloxyalkyl groups are allyloxymethyl, 2 - (but-3 * -enyloxy) -hexyl, and the like.

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

The term "phenoxyalkyl group" denotes groups of the formula p-O-R'-, wherein f represents a phenyl group and E 'represents the alkyl group substituted by the phenoxy group, as defined above, and includes, for example, phenoxymethyl, phenoxyhexyl, 5- phenoxy-3-methylpentyl groups and the like.

The term "phenylthioalkyl group" denotes groups of the formula ^ -S-Rr-, wherein fen a phenyl group and B * represent the alkyl group substituted by the phenylthio group, as defined above, and includes, for example, phenylthiomethyl-, phenylthio-t hy 1-i ** phenyl thio-1-methyl hutybutyl group and the like.

The term "substituted phenoxyalkyl group" denotes groups of the formula "-O-R" - where R 'represents the alkyl group substituted by the phenoxy group as defined above and 1 represents a phenyl group having one or two substituents, independently selected from the group consisting of fluorine, chlorine, bromine, iodine, alkyl and / or alkoxy groups. Typical examples of the substituted phenoxyalkyl groups are 1-fluorophenoxymethyl, 2-iodo-5-bromophenoxymethyl, 2 - (2,5-30 dimethylphenoxy) -ethyl-, 4-C 2-methoxy-4-chlorophenoxy) -1-methylbutyl groups and the like.

The term "substituted phenoxythioalkyl group" denotes groups of the formula ψ'-S-S1-, wherein R 'represents the alkyl group substituted by the phenylthio group, as defined above, and represents a phenyl group having one or two substituents, independently selected from the group consisting of fluorine, chlorine, bromine, iodine, alkyl and / or alkoxy groups Typical examples of the substituted phenylthioalkyl groups are 1-fluoro-phenylthiomethyl, 2-iodo-5-bromophenylthiomethyl, AO 2- (2,5-dimethylphenylthio) -ethyl-, 4- (2-hexoxy-4-chlorophenylthio) - 81 03 0 24 * 10 * 1-methylbutyl groups and the like.

The term "unsubstituted fatty acid *" denotes carboxylic acids of the formula R'COOH, wherein R * represents an alkyl group of 1 to 20 carbon atoms.

5 The term "low molecular weight primary alcohol" * denotes • a primary alcohol with a molecular weight of less than 70 * such as, for example, methanol * ethanol and the like ·

As noted above, the products of formula VI are useful for combating fungi *, in particular fungal infections in plants; compare Belgian patent specification no. 871,668. For example, the compounds have been used as fungicides against fungal diseases such as downy mildew, for example Plasmopara viticola (grapes) and Peronospora parasitica (cabbage and Brussels sprouts), late mildew, for example Phytophthora 15 infestans (tomatoes and potatoes) and crown and root rot, for example, Phytophthora.

These compounds are particularly useful fungicides because they cure certain types of fungus infections that have occurred. This allows an economical use of the fungicides according to the invention, because they do not have to be applied to the plants before a fungus infection has actually occurred · A preventive program for applying fungicides against potential fungus infection is so not necessary.

When used as fungicides, the compounds are applied in amounts effective for use as fungicides. on fungi and / or habitats thereof, such as vegetative hosts and non-vegetative hosts, for example animal products.

The amount used will of course depend on various factors, such as the host, the type of fungus and the particular compound applied. As with most pesticidal compounds, the compounds are not usually applied uncut, but are generally incorporated into conventional biologically inert extenders or carriers which are commonly used to facilitate dispersion of the active fungicidal compounds taking into account the fact that , that the preparation and the method of application can influence the activity of the fungicide. * Thus, the compounds can be processed and applied into preparations, such as, for example, granules, powdered dusts, spray powders, emulsifiable concentrates, 40 solutions or one of the many other known types of preparations 8103024 11 t * depending on the desired method of application

Spray powders are in the form of finely divided particles, which are readily dispersible in water or other dispersant · These formulations usually contain about 5 to 80% of fungicide and otherwise inert material, which include dispersants, emulsifiers and wetting agents · The powder can be applied to the soil as a dry material or, preferably, as a suspension in water · Typical examples of carriers are earthy, kaolin clays, silicon oxides and other highly absorbent, wettable, inorganic diluents · Typical examples of wetting, dispersing or emulsifiers are: the aryl and alkaryl sulfonates and the sodium salts thereof, alkyl amide sulfonates such as fatty methyl taurides; alkylaryl polyether alcohols, sulfated higher alcohols and poly-15 vinyl alcohols; epoxyalkane polymers, sulfonated animal and vegetable oils; sulfonated petroleum derived oils, fatty acid esters of polyhydric alcohols and the epoxyethane addition products of such esters and the addition products of long chain mercaptans and epoxyethane. Many other types of useful surfactants are commercially available

The surfactant, when used, usually makes up 1 to 15% by weight of the fungicidal composition.

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

Suitable liquid concentrates are emulsifiable concentrates, which are homogeneous liquid or pasty preparations, which are readily dispersible in water or other dispersive medium and may consist entirely of fungicide with a liquid or solid emulsifying agent or may also be a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents · Before use, these concentrates are dispersed in water or other liquid vehicle ifO and usually as a mist on the surface to be treated. 81 03 0 24

f V

12 fitted flat.

Other useful preparations for fungicidal applications are simple solutions of the active fungicide in a dispersive medium in which it is completely soluble in the desired concentration, such as acetone, alkylated naphthalenes, xylene or other organic solvents. Granular preparations in which the fungicide is present on relative coarse particles as a carrier are particularly useful for air distribution or for penetrating a dense upright crop crop. Pressure-sprayable preparations, in particular aerosols, in which the active ingredient is dispersed in finely divided form thanks to the evaporation of a low-boiling dispersant medium, such as the Freons, as a carrier. All these techniques can be used for the preparation of preparations and the application of fungicides are well known in the art.

The optimum weight percentages of the fungicide (active agent) may vary depending on the manner in which the composition is to be applied and the particular type of composition, but generally are from 0.5 to 95% by weight of the fungicide composition.

The fungicidal preparations can be prepared and used with other active ingredients, such as other fungicides, insecticides,. nematocides, bactericides, plant growth regulators, fertilizers, etc.

A better understanding of the invention can be obtained by the following non-limiting examples. The term "room temperature" as used herein denotes a temperature of about 20 ° C to 25 ° 0. The term "percent" or denotes percent by weight, while the term "mole" denotes gram mole. The term "equiv. 30 valent "indicates an amount of reagent in moles equal to the number of moles of the preceding or following reagent reported in the preparation or example in terms of moles or determined weight or volume. Unless clearly stated otherwise, racemic mixtures and / or diastereomeric mixtures are used as starting materials and corresponding racemic mixtures and / or diastereomeric mixtures are obtained as product The examples are repeated as necessary to provide sufficient amounts of the starting materials for the subsequent preparation procedures and examples. ifO ting EA indicates elemental analysis for both the calculated and 81 03 0 24 13 the values found in weight percent.

As far as mentioned, the magnetic proton nuclear magnetic resonance spectra (p * m * r *) are determined at 60 MHz and the signals are described as singlets (s) j wide singlets (bs), doublets Cd), 5 double doublets (dd), triplets (t), double triplets (dt), quartets (q) and multiplets (m).

Example I

This example serves to illustrate step (a) of the process according to the invention and the hydrolysis of the salt of the formula III or the acid thereof, which optionally is optionally used.

In this example, 15 ml of anhydrous dimethoxyethane were mixed with 1 * 98 g (0.022 mole) of 2-methyl-2-propanethiol and 1.18 g (0.02 mole) of sodium methanolate. The mixture was refluxed for 1 hour and then cooled to room temperature, then 4.10 g (0.02 mol) of 3- (2 * 6-dimethylphenylamino) - / - butyrolactone were added. The resulting mixture was refluxed for 1 -1/4 hours, after which about 0. 2 g of sodium methanolate and were added, reflux was continued for an additional hour. * At the end of this period, the mixture was cooled * 20 and 20 ml of ice water were added. The mixture was then extracted with toluene * and the remaining aqueous phase. was acidified with glacial acetic acid to a pH of 6 and extracted with dichloromethane * The dichloromethane extract was washed three times with water, dried over magnesium sulfate and evaporated to give 2.80 g of 25 l-carboxy-1- (2,6-dimethylphenylamino) -3- tert-butylthiopropane as a viscous oil was obtained.

Following the same procedure but using the required lactone starting materials instead of the 3- (2 »6-dimethylphenylamino) _-butyrolactone, the following compounds were similarly prepared: 1-carboxy-1 - (2, 3,6-trimethylphenylamino) -3-tert-butylthiopropane; 1-carboxy-1- (2-methoxy-6-methylphenylamino) -3-tert-butylthiopropane, and 1-carboxy-1-naphthylamino-3-tert * butylthiopropane * 35 By following the same procedure but instead of To prepare thiolate in situ, the thiolate salts: potassium allyl thiolate, ammonium benzyl thiolate and sodium naphthyl thiolate were reacted directly with each of the butyrolactone starting materials used above, similarly employing the corresponding thio-40 propylene, thiobenzene and thionaphthalene analogs of each of the above 8103024 fur 'listed products were obtained ·

Example II

This example illustrates the second step (b) of the process, as indicated in the reaction scheme of Figure 1.

In this example, 1.1 g (0.0037 mol) of 1-carboxy-1- (2,6-dimethylphenylamino) -3-tert-butylthiopropane were dissolved in 10 ml of dichloromethane, which contained 0.56 g (0, 0554 mole) of triethylamine · The mixture was cooled to 0 ° C, 0.44 g (0.0041 mole) of methoxyacetyl chloride were mixed dropwise with this mixture and the resulting mixture was stirred for an additional 10 minutes at 0 ° C · The mixture was then warmed to room temperature for 30 minutes and then poured into ice water. The dichloromethane phase was extracted, washed once with aqueous hydrochloric acid and twice with water, then dried over magnesium sulfate and evaporated * to give 1.3 g of 15 l-carb oxy-1 - [N- (2,6-dimethylphenyl) -methyl hoxy ac e et amid o J-3-1 er t-buty 1-thiopropane, which contained a small amount of the 1-methoxyacetoxy-carbonyl derivative, when an oil was obtained · The degree of conversion achieved for this step, based on the carboxylic acid starting material was about 95%. Likewise, following the same procedure but using each of the other products of Example 1 as starting materials, the corresponding methoxyacetamide derivatives of the formula 5 were prepared.

Following the same procedure, but replacing the methoxyacetyl chloride with chloroacetyl chloride, cyclopropyl carbonyl chloride, bengoyl chloride and 2,3-epoxybutyryl chloride, similarly the corresponding chloroacetamido, cyclopropylami-do, benzoylamido and 2,3-epoxybutyramido respectively analogues of each of the above compounds have been prepared.

Example III

This example serves to illustrate the third step (c) of the method according to the invention, as explained with reference to the reaction scheme of fig. 1.

In this example, 1.7 g (0.0046 mol) of the 1-carboxy-35 l - [N- (2, β-dimethylphenyl) -H-methoxyacetamido,] - 3-tert-butyl thiopropane product prepared according to example II dissolved in 10 ml of anhydrous dichloromethane · The mixture was then cooled to 0 ° C, whereupon 0.317 g (0.0023 mol) of phosphorus trichloride were added.

O

mixed. The mixture was stirred at 0 ° for 20 minutes and then warmed to room temperature and stirred for 1 hour at room temperature, 8103024 15 t, then hei; was quenched by addition of ice * The solution was then decanted to remove a small amount of solid precipitate »that had formed» The dichloromethane phase was then removed and successively with water »a 5% w / w aqueous sodium carbonate solution» washed twice with water »with 1 n * aqueous hydrochloric acid and then twice more with water * The washed mixture was then dried over magnesium sulfate and evaporated * to yield 1 g of 3- (N-methoxyacetyl-N-2,6-dime-) thylphenylamino) - / - butyrothiolactone as an oil was obtained * The oil was then crystallized from isopropanol * The infrared spectra and magnetic proton nuclear spin resonance spectra of the crystalline product were determined and found to be identical with the spectra of a comparative sample of 3-Or -methoxyacetyl-N-2, β-dimethylphenylamino) - / - butyrothiolactone * 15 Following the same procedure but the other products

of Example II as starting materials, the corresponding butyrothiolactone derivatives were prepared in the same manner * Example UIA

This example serves to illustrate the third step (c) of the process of the invention as illustrated by the reaction scheme of FIG. 1 using a different cyclizing agent than that used in Example III.

In this example, a solution »containing 0.24 g sulfuric acid» 4 ml toluene and 6 ml acetic acid »was added to 2.35 moles of 1-carboxy-1- [N- (2,6-dimethylphenyl) -N-methoxyacetamido ] -3-tert-butylthiopropane * The mixture was refluxed for 2 hours (about 110 ° C) then cooled and washed twice with 10 ml of water * (A small amount of dichloromethane was added to prevent washing during washing precipitating solids). The washed mixture was then evaporated to dryness at 50 ° C to obtain 3 * 65 g of 5- (N-methoxy-acetyl-N-2, β-dimethylphenylamino) - / - butyrothiolactone as a solid. * The aqueous washings were combined and extracted with dichloromethane. The dichloroethane extract was evaporated to dryness, yielding an additional 0.27 g of 35 3- (N-methoxyacetyl-N-2, β-dimethylphenylamino) - / - butyrothiolactone as a solid *

Following the same procedure but using the other products of Example II as starting materials, the corresponding butyrothiolactone derivatives are obtained in a similar manner.

81 03 0 24 * '16

Example IV

Examples IV to VI serve to illustrate the process of an embodiment wherein the salt of formula 3 is acylated directly without prior conversion to the acid.

3 In this example, 9 * 5 g (0 * 1 mole) of 2-methyl-2-propethiol was added to a suspension under stirring at room temperature, containing 6 g (0.1 mole) of sodium methanolate in 70 ml of anhydrous 1 »2 -dimethoxyethane. The resulting mixture was stirred at room temperature for about 30 minutes (giving rise to the formation of sodium 2-ethyl-2-propanethiolate), after which 20.5 g (0.1 mol) 3- (2,6-dimethylphenylamino) - Butyrolactone was added. The mixture was refluxed until the suspension turned into a clear solution (about one hour). The solution was evaporated to remove the solvent and the methanol formed as a by-product, the sodium salt of et- (2,6-dimethylphenylamino) -a- (2-tert-butylthioethyl) -acetic acid of the formula 3 was obtained as a residue.

Following the same procedure, but using the corresponding 3-arylamino or 3-substituted arylamino - / - butyrolactone onion t-20 starting materials, the following compounds were prepared in a similar manner: sodium salt of a- (phenylamino) -a- (2 -tert.butylthioethyl) -acetic acid, sodium salt of a- (4-fluorophenylamino) -a- (2-tert-butylthioethyl) -acetic acid, sodium salt of a- (2-iodophenylamino) -a- (2-tert-butylthioethyl) -acetic acid, sodium salt of a- (2,6-dichlorophenylamino) -a- (2-tert-butylthioethyl) -acetic acid, sodium salt of a- (2-methoxyphenylamino) -a- (2-tert-butylthioethyl) -30 acetic acid, sodium salt of a- (2-methyl-4-pentylphenylamino) -a- (2-tert-butyl-thioethyl) -acetic acid, sodium salt of a- (2, β-dibromophenylamino) -a- (2-tert-butylthioethyl) acetic acid and sodium salt of a- (2-methyl-3-chlorophenylamino) -a- (2-tert-butyl-thioethyl) -acetic acid, respectively.

Following the same procedure, but replacing the in-situ prepared sodium 2-methyl-2-propanethiolate with potassium hexyl enyl thiolate, calcium di- (methyl thiolate) and ammonium benzyl thiolate, the corresponding analogue was likewise 81 03 024 f 17 salted products of any of the above products.

Example V

In this example, the residual sodium salt of α- (2,6-dimethylphenylamino) -a- (2-tert-butyl-5 thioethyl) -acetic acid (of the formula 3) obtained as a residue was redissolved in 250 ml of dimethoxyethane and Refluxed # After this, 7 * 5 g (0.1 mol) Ν, Ν-dimethylformamide was added followed by the addition of 9.5 g (0.1 mol) acryioyl chloride at which time the solution turned light brown. The mixture was cooled to room temperature, then a further 7.5 g (0.1 mol) Ν, Ν-dimethylformamide was added followed by the addition of another 9.5 g (0.1 mol) acryioyl chloride. The mixture was then refluxed for 1.1 / 2 hours and then evaporated in vacuo to remove the solvent. The residue was suspended in diethyl ether, filtered over diatomaceous earth and evaporated, the mixed acrylic acid -a- [N- (2,6-dimethylphenyl) -N-acryloylamino] -a- (2-tert-butylthioethyl) -acetic acid- anhydride as a residue was obtained.

Following the same procedure using the other products of Example IV as starting materials, the following compounds were prepared in a similar manner: acrylic acid-α- (N-phenyl-N-acryloylamino) -a- (2-tert-butylthioethyl) - acetic anhydride, acrylic acid a- [N- (1 * -fluorophenyl) -N-acryloylamino] -a- (2-tert-butyl-25 thioethyl) -acetic anhydride, acrylic acid-a- [N- ( 2,6-dichlorophenyl) -N-acryloylamino] -a- (2-tert-butylthioethyl) -acetic anhydride, acrylic acid-a- [N- (2-methoxyphenyl) -N-acryloylamino] -a- (2 -tert-butyl-thioethyl) -acetic acid anhydride, acrylic acid-a- [N- (2-methyl-if-pentylphenyl) -N-acryloylamino] -a- (2-tert-butylthioethyl) -acetic acid anhydride, acrylic acid -a- [N- (2,6-dibromophenyl) -N-acryloylamino] -a- (2-tert-butyl-thioethyl) -acetic anhydride and acrylic acid -a- [N- (2-methyl-3-chlorophenyl) ) -N-acryloylamino] -a- (2-35 tert-butylthioethyl) -acetic anhydride ·

By following the same procedure but instead of the acryioyl chloride acetyl chloride, dichloroacetyl chloride, • hydroxyacetyl chloride, methoxyacetyl chloride, methylthioacetyl chloride, phenylthioacetyl chloride, phenoxyacetyl chloride, 2,6-dimethylphenyl-2 * 0 acetyl chloride, 2 * thoxyphenylacetylchloride and 2,5-epoxy - 81 03 024 '18 * chloride, the corresponding diacyl derivatives of each of the above compounds were prepared »for example acetic acid-a- [N- (2,6-dimethylphenyl) -acetamido] -a- (2-tert-buty1- thioethyl) -acetic anhydride »5 dichloroacetic acid-a- (N-phenyl-dichloroacetamido) -a- (2-tert-butyl-thioethyl) -acetic anhydride» hydroxyacetic acid- <x- [N- (li-fluorophenyl) -hydroxyacetainido] -a- (2-tert-butylthioethyl) -acetic acid anhydride »methoxyacetic acid-a- [N- (2,6-dimethylphenyl) -methoxyacetamido] -a-10 (2-tert-butylthioethyl) -acetic acid- anhydride »methylthioacetic acid-a- [N- (2» 6-dichlorophenyl) -methylthioacetamido] -a- (2-tert-butylthioethyl) -acetic anhydride »f enylthioacetic acid-a- [N- (2-methoxyphenyl) -phenylthioaeeetamido] -a- (2-tert-butylthioethyl) -acetic anhydride, phenoxyacetic acid-a- [N- (2-methyl-4-pentylphenyl) -phenoxyacetamido] -a- (2-tert-butylthioethyl) -acetic anhydride »(2,6-dimethylphenyl) -acetic acid-a- [N- (2» 6-dibromophenyl) - (2,6-dimethylphenyl) -ace etami do] -a- (2-tert-butylthioethyl) -acetic acid anhydride »20 (-ethoxyphenyl) -acetic acid-a- [N- (2-methyl-3-chlorophenyl) - (if- ethoxyphenyl) -ac edamido] -a- (2-tert-butylthioethyl) -acetic anhydride »2,3-epoxybutyric acid-a- [N- (2,6-dimethylphenyl) -2» 3-epoxybutyramido] -a- (2-tert #butylthioethyl) -acetic anhydride »etc. ·

Example VI

In this example, the residue obtained in Example V was acrylic acid-a- [N- (2,6-dimethylphenyl) -N-acryloylamino] -a (2-tert-butylthioethyl) -acetic anhydride with 200 ml dimethoxyethane mixed * and slowly 1 * 2 g (0.3 mol) of phosphorus chloride were added. The resulting mixture was cooled to about 8 ° C and then stirred at room temperature overnight (about 12 hours). Analysis by thin layer chromatography of a small sample thereof revealed the presence of some unconverted starting material (i.e., the butylthiopropane derivative) and two other products. The reaction mixture was then refluxed for 2 hours and then evaporated to remove the solvent. The residue was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution to neutralize the acidic constituents then washed with water and dried over magnesium sulfate. The dichloromethane was then removed by evaporation to give an oily residue. 81 03 024 19. The oily residue was then chromatographed on 250 g of silica gel and eluted successively with petroleum ether, 95% petroleum ether and diethyl ether; 90% petroleum ether and diethyl ether, 75 # petroleum ether and diethyl ether. The silica gel column was further eluted with 50% petroleum ether and diethyl ether to yield about 3 g of 3- (N-acryloyl-N-2,6-dimethyl-phenylamino) - / - butyrothiolactone.

Following the same procedure, the products of Example V were similarly converted to the corresponding 10-butyrothiolactone derivatives, for example: 3- (N-acryloyl-N-2,6-dichlorophenylamino) - / - butyrothiolactone, 3- [N- acryloyl-N- (2-methyl-3-chlorophenyl) -amino] - / - butyrothiolactone, 3- (N-dichloroacetyl-N-phenylamino) - / - butyrothiolactone, 3-C N-methoxyacetyl-N-2 ' 6'-dimethylphenylamino) - / - butyrothiolactone, 3- (H-phenylthioacetyl-N-21-methoxyphenylamino) - / - butyrothiolactone, 3- [N- (2,6-dimethylphenyl) -acetyl-N- (2 , 6-dibromophenyl) -amino] - / - butyrothiolactone, 3- [N- (2,3-epoxybutyryl) -N- (2,6-dimethylphenyl) -amino] - / - butyrothiolac tons, etc ··

Example VII

In this example, the procedures of Examples II and V are repeated, however, using the corresponding acyl bromides instead of the acyl chloride. Samples of the resulting products of formula 5 are then converted to the corresponding compounds of formula 6 using the procedure of Example III and the procedures of Example IIIA.

Example VIII

This example serves to illustrate another embodiment of the method of the invention.

A. A solution of 11.89 g of 3- (N-2} 6-dimethylphenylamino) - / - butyrolactone in dimethoxyethane was added to 6.5 g of sodium tert-butyl thiolate. - boiled and gutted. The residue was dissolved in water, acidified with hydrochloric acid and extracted with dichloromethane. The organic phase was collected dried (MgSO4) and stripped to give 15 * 2 g of viscous oil (the IR spectrum shows the presence of - CO ^ H) · B. 5 g of the oil is stirred in 10 ml (15 * 7 g) of 40 phosphorus trichloride at room temperature for 2 days · 8103024 t * - 20

The excess phosphorus trichloride was stripped at 60 ° C and the residue was dissolved in dichloromethane, washed with water and dried. The residue was purified on a silica gel column to yield 1.31 g of 3 - (N-2,6-dimethylphenylamino) - 3-Butyrothiolactone was obtained (yield of 3 * 8%) * C * The product from Step B was then acylated using the procedure described in Example II to give the 3- (N-methoxyacetyl-N-2, 6-dimethylphenylamino-y-butyrothiolactone was obtained.

It will be understood that many modifications and variations of the invention, as described above and defined in the claims below, are possible without departing from the essence and scope of the invention.

8103024

Claims (17)

21 1 · Process for the preparation of compounds of the formula 6, wherein Ar represents an aryl group or substituted aryl group with 1 to k substituents, which substituents independently of each other are fluorine, chlorine, bromine, iodine atoms, alkyl and / or alko - A xy groups, and S are an alkyl or alkoxy group, cycloalkyl group with 3 to 6 carbon atoms, epoxyalkyl, alkenyl, alkenyloxy or hydroxyalkyl group, haloalkyl group with 1 to 3 halo substituents and 1 to 6 carbon atoms, alkoxyalkyl, alkylthioalkyl Phenylthioalkyl or phenoxyalkyl group or a substituted phenylthioalkyl or substituted phenoxyalkyl group having 1 or 2 substituents on the ring, which substituents independently of one another include fluorine, chlorine, bromine, iodine, alkyl and / or al 2 koxy groups, and R represents a hydrogen, chlorine or bromine atom, an alkyl or phenyl group or substituted phenyl group with one or two substituents on the ring, which substituents are independently n are each other fluorine, chlorine, bromine atoms and / or alkyl groups, characterized in that (a) the corresponding arylamino - / - butyrolactone of the formula 1, * 2 in which Ar and R have the above meaning under reaction contacting active conditions with a thiolate salt, and either (b) contacting the product of step (a), optionally after hydrolysis, with an acyl halide of the formula k * wherein R has the meaning above and X represents chlorine or bromine and (c) contacting the product of step (b) with a cyclizing agent under reactive conditions to form a compound of formula 6, or performing step (c) before step (b) to form the corresponding thiolactone as intermediate and the thiolactone intermediate acylates according to step (b) to form the compound of the formula 6.2 * Process according to claim 1, characterized in that Ca) is an arylamino-γ-butyrolactone of the formula 1 under reactive om conditions with a thiolate salt into the corresponding salt of 1- (Ar-amino) -1-carboxy-3-thiopropane, (b) convert the salt of the "h-CAr-amino) -1-carboxy-3-thiopropane with the acyl halide of formula k and (c) the N-acylamino-k0 product of step (b) under reactive conditions 81 03 0 24 with a cyclizing agent * which esterifies a saturated fatty acid with a primary alcohol containing a will produce low molecular weight * 3 * Process according to claim 1, characterized in that (a) an arylaraino - / - butyrolactone of the formula 1 is converted into the corresponding salt of 1 - (Ar-amino) -1-carboxy-3-thiopropane * (b) contacting the salt with an acid under reactive conditions to form the corresponding free 1- (Ar-amino) -1-carboxy-3-thiopropane, (c) 1 - (Ar-amino) -1-carboxy-10 3-thiopropane reacts with the acyl halide of the formula ^ and (d) the N-acylamino product of step (c) under reactive conditions contacting a cyclizing agent * capable of converting carboxylic acids or esters into acid halides * Process according to one or more of the preceding claims, characterized in that the compound of the formula 1 has the 3- (2,6 -dimethylphenylamino) - / - butyrolactone is * 5 * Process according to one or more of the preceding claims, characterized in that the thiolate salt is an alkali metal thiolate * 20 6 * Process according to one or more of the preceding claims, characterized in that the thiolate salt is sodium 2-methyl-2-propanethiolate * 7 * Process according to one or more of the preceding claims, characterized in that the acylation with the acyl-halide of the formula k is carried out at temperatures within the range of about 0 ° C to 120 ° C. 8. Process according to one or more of the preceding claims, characterized in that step (a) is carried out in an inert organic liquid. * Process according to one or more of the preceding claims, characterized in that the acylation with the acyl halide of the formula k is carried out in an inert organic solvent * 10. Process according to one or more of the preceding claims, characterized in that cyclization is carried out in an inert organic solvent * 11. Process according to claim 2, characterized in that the salt of the 1- (Ar-amino) -1-carboxy-3-thio-propane in step (b) is added with about 2 to 2.2 mol of the acyl halo - contact kO gene per mole of the salt. 8103024 The process according to claim 3, characterized in that the free 1- (Ar-amino) -1-carboxy-3-thiopropane is treated in step (c) with about 1 to 1.1 moles of the acyl halide per mole of the 1- (Ar-amino) -1-carboxy-3-thiopropane Method according to claim 2, characterized in that an arylamino lactone of the formula 1, wherein Ar p and B have the above meaning, in reactive conditions in an inert organic liquid carrier at temperatures within the range of about 20 to about 200 ° C, contacting with a thiolate salt of the formula MSB, wherein M is an alkali metal cation and B is an alkyl, alkenyl or arylalkyl group to form the corresponding compound of formula 3, wherein Ar, B and B have the above meaning, (b) the compound of formula 3 is an inert organic solvent under reactive conditions at temperatures within the contact range of about 0 to 120 ° G t with an acid halide of the formula 4 * in which E has the above meaning and X represents a chlorine or bromine atom, to form the corresponding acylated product of the formula 5 wherein 12 3 Ar, R, R and E have the above meanings and R represents hydrogen or 1f, wherein R is a substituent as defined! for R1 and (c) the acylated product of step (b) in an inert organic solvent under reactive conditions, in contact with a cyclizing condensing agent, which will effect esterification of a saturated fatty acid with a low molecular weight primary alcohol . 14. Process according to claim 3, characterized in that (a) an arylaminolactone of the formula 1 in which 2 Ar and R have the aforementioned meaning, in an inert organic liquid carrier under reactive conditions at temperatures within the range of about 20 up to 200 ° C with a thiolate salt of the formula MSB, wherein M represents an alkali metal cation and R represents an alkyl, alkenyl or arylalkyl group, to form the corresponding compound of the formula 3 * o 35 wherein Ar, M , R and B have the aforementioned meaning, (b) contact the compound of the formula 3 with an acid under reactive conditions to form the corresponding 1-arylamino-1-carboxy-3-thiopropane, (c) the 1- arylamino-1-carboxy-3-thiopropane in an inert organic solvent, under reactive conditions at temperatures within the range of about 8103024 from 2½ to 120 ° C, with an acyl halide of the formula mi wherein R is the has said meaning and X represents a chlorine or bromine atom, to form the corresponding acylated product of formula 5, wherein Ar, R, R and R have the meaning mentioned and R represents a hydrogen atom or "1f -CR 1", where R. a substituent as defined for 4 R and (d) the acylated product of step (c) in an inert organic solvent under reactive conditions contacting a cyclizing agent, which esterifies saturated fatty acid with a primary alcohol with will cause low molecular weight. Process according to claim 13 or 1, characterized in that 1,2-dimethoxyethane and / or diglyme are used as the inert organic liquid for step (a) and glacial acetic acid as the inert organic solvent for the acylation and ring closure, dichloromethane, 1,2-dichloroethane, toluene or a mixture thereof. 16. Process according to any one of claims 13 to 15, characterized in that 1,2-dimethoxyethane is used as the inert organic liquid in step (a) and dichloromethane as the inert organic solvent in the acylation and the ring closure. Process according to one or more of Claims 13 to 16, characterized in that the cyclising condensation agent used is phosphorus trichloride or mixtures of glacial acetic acid with a minor amount of sulfuric acid. Process according to one or more of the preceding claims, 2, characterized in that R represents hydrogen. 19. Process according to one or more of the preceding claims, characterized in that (2,6-dimethylphenylamino) - / - butyrolactone is used as the starting material with the formula and methoxyacetyl chloride as acyl halide. 1 2 20. A compound of the formula V wherein Ar, R and R have the meaning as defined in claim 1 and R an alkyl, alkenyl or arylalkyl group and R a hydrogen atom or the radical "1, -CR λ i 1 .. ... proposals, where R has the meaning mentioned for R. Compound according to claim 20, characterized in that R represents a tert-butyl, allyl or benzyl group. 22. A process for the preparation of a compound according to claim 20, characterized in that a compound of the formula 8, wherein Ar, S and R is the compound of claim 20. have said meaning and M represents a proton or cation and m * indicates the valence of M under reactive conditions contacts with an acyl halide of the formula IV, wherein X Ί represents a chlorine or bromine atom and R represents the meaning defined in claim 20 possession A process for preparing a compound of formula 2 in which Ar and R have the meaning as defined in claim 1, characterized in that (a) a compound of the formula 1, wherein Ar and R have the meaning mentioned, reacts with a thiolate salt under reactive conditions and (b) treats the product obtained according to step (a) with a reagent capable of esterifying a saturated fatty acid with a primary alcohol with a low molecular weight. 2k. Process according to claim 23, characterized in that the product of step (a) is converted into acid * before step (b). · Process according to claim 23 or 21, characterized in that a 2-methyl-2-propane thiolate is used as the thiolate salt and phosphorus trichloride as the reagent for step (b). 26. Process according to one or more of claims 23 to 25, characterized in that Ar represents the 2,6-dimethylphenyl group. 25 ****** 8103024