GB2078741A

GB2078741A - Process for Preparing Gamma- butyrothiolactone Derivatives and Intermediates Therefor

Info

Publication number: GB2078741A
Application number: GB8119334A
Authority: GB
Original assignee: Chevron Research and Technology Co; Chevron Research Co
Current assignee: Chevron USA Inc
Priority date: 1980-06-23
Filing date: 1981-06-23
Publication date: 1982-01-13
Also published as: GB2078741B; IT1136849B; ES8304115A1; ES503313A0; DD209443A5; FR2491069B1; FR2491062B1; NL8103024A; ES513071A0; FR2485013B1; ES8304114A1; DE3123864A1; CH648307A5; FR2485013A1; FR2491069A1; ES513070A0; DD160416A5; FR2491062A1; ES8300105A1; IT8122482A0

Abstract

3-(N-aryl-N-acylamino)gamma- butyrothiolactones having fungicidal activity are prepared by a process which comprises in a preferred embodiment cleaving the corresponding arylamino-gamma- lactone with a thiolate salt to yield the corresponding arylamino-thiolalkane carboxylate salt; hydrolyzing the salt and then acylating the resulting acid to yield the corresponding N-acyl-N- aryl-amino product. This product is then cyclized to yield the required compound. Alternatively, the order of the acylation and cyclization can be reversed. Also novel compounds of the formula <IMAGE> wherein Ar is optionally substituted aryl, R is alkyl, alkenyl or aryl-alkyl, R<1> are various substituents, R<2> is H, Cl, Br, I, alkyl or optionally substituted phenyl and R<3> is H or <IMAGE> wherein R<1> is as defined above.

Description

SPECIFICATION Process for Preparing Gamma-butyrothiolactone Derivatives and Intermediates Therefor This invention relates to processes and intermediates for preparing 3-(N-aryl-N-acylamino)gamma butyrothiolactones.

3-(N-aryl-N-acylamino)-gamma butyrothiolactones are known compounds having fungicidal activity and are described in Belgian Patent 871,668. In the Belgian patent the compounds are prepared via the amination (anilination) of a 3-halo-gamma-butyrothiolactone followed by acylation with the appropriate acyl halide.

A discussion of the preparation of certain un-substituted thiolactones can be found in an article by Truce et al appearing in the Journal of Organic Chemistry, Vol. 28, p. 964 (April 1963).

The present invention provides an improved process for preparing high yields of 3-(N-aryl-Nacylamino)-gamma thiobutyrolactones and the intermediates produced thereby.

In accordance with one aspect of the invention, the process comprises the steps of: (a) contacting a 3-(aryl or substituted arylamino)-gamma-butyrolactone or a 5-substituted derivative thereof with a thiolate salt under reactive conditions to yield the corresponding 1-(aryl or substituted aryl)amino 1 -thio-alkane carboxylate salt and acidifying the salt to yield the corresponding carboxy acid; and (b) contacting the product of step (a) with an acyl halide under reactive conditions to yield the corresponding acyl amino derivative; and (c) contacting the product of step (b) with a cyclizing agent, which will effect esterification of a saturated fatty carboxylic acid with a low molecular weight primary alcohol, to yield the corresponding 3-(N-aryl or substituted aryl-N-acylamino)-gamma-butyrothiolactone or 5-substituted derivative thereof.

Alternatively, the order of steps (b) and (c) can be reversed, thus first cyclizing the intermediate of step (a) followed by acylation.

In accordance with another aspect of the invention, the process of the present invention can be conveniently schematically represented by the following overall reaction scheme:

wherein Ar is aryl or substituted aryl having from one through four substituents independently selected from the group of fluoro, chloro, bromo, iodo, lower alkyl, or lower alkoxy; R is lower alkyl (preferably t-butyl); lower alkenyl (preferably allyl) or arylalkyl (preferably benzyl); R1 is lower alkyl; lower alkoxy; cycloalkyl having three through six carbon atoms (preferably cyclopropyl); lower epoxyalkyl having from 2 through 6 carbon atoms including one or two epoxy groups; lower alkenyl; lower alkenyloxy; hydroxy-lower alkyl (preferably hydroxymethyl); haloalkyl having one through three halo substituents and from one through six carbon atoms; lower alkoxyalkyl, lower alkylthioalkyl; phenylthio-lower alkyl (preferably phenylthiomethyl); phenoxy-lower alkyl (preferably phenoxymethyl); substituted phenylthio-lower alkyl (preferably substituted phenylthiomethyl); or substituted phenoxy-lower alkyl (preferably substituted phenoxymethyl) having one or two ring substituents independently selected from the group of fluoro, chloro, bromo, iodo, lower alkyl, or lower alkoxy; and R2 is hydrogen, chloro, bromo, lower alkyl, phenyl or substituted phenyl having one or two substituents independently selected from the group of fluoro, chloro, bromo or lower alkyl; R3 is hydrogen or

wherein R1 is selected from the same group of substituents as R.

M is an inorganic cation, preferably an alkali metal cation, and m corresponds to its valence and X is chloro or bromo.

Step 1 of the process can be conveniently conducted by contacting the appropriate compound of formula A having the desired Ar and R2 substituent with the thiolate of formula B, preferably in a suitable organic solvent under reactive conditions.

Typically, this process is conducted at temperatures in the range of about from 20 to 2000C preferably about from 50 to 800C for about from 1 to 8 hours preferably about from 1 to 4 hours.

Typically, about from 1 to 1.5 mols, preferably about from 1 to 1.25 mols of compound of formula B (based on the thiolate content) are used per mol of compound of formula A.

Where an organic solvent is used, the solvent is generally only a solvent for reactant A. Suitable inert organic solvents which can be used include, for example, dimethoxyethane, toluene, tetrahydrofuran, dimethyl formamide and the like and compatible mixtures thereof. Preferably dimethoxyethane is used as the solvent. Typically, a liquid medium ratio of about from 1 to 3 mols of reactant A per liter of solvent is used.

Generally, best results are obtained by conducting the process at temperatures in the range of about from 50 to 800C using about from 1 to 1.10 mol of B per mol of A in dimethyoxyethane.

Suitable thiolates of formula B which can be used include, for example, alkali metal thiolates e.g., sodium 2-methyl-2-propanethiolate, potassium 2-methyl-2-propanethiolate; alkali earth thiolates, calcium bis(alkylthiolate), ammonium thiolates; quaternary amine thiolates, e.g.

tetramethylammonium, benzylthiolate and the like. In terms of yields where alkyl mercaptides are used, tertiary alkyl mercaptides are preferable to secondary and primary alkyl mercaptides, and secondary alkyl mercaptides are preferable to primary alkyl mercaptides. Generally, 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 alkoxide (e.g., sodium methoxide).

The compounds of formula A are known compounds and can be prepared by known procedures, including, for example, via the reaction of the corresponding aryl or substituted aryl amine with the corresponding 3-chloro or 3-bromobutyrolactone, as, for example, described in Belgian Patent 871,668; U.S. Patent 3,933,860 or U.S. Patent 4,165,322.

The product of step 1 is the corresponding M salt of the acid of formula I. Before conducting the second step of the present process it is very much preferred to remove any unreacted compound (A) from the reaction product. This can be conveniently effected by extraction since compound (A) is generally insoluble in water whereas compound (I) is soluble in water.

Salt (I) can then be reacted with the acyl chloride or bromide (C) according to step 2 of the present invention or preferably is first hydrolyzed to the acid (formula I) via treatment with a weak acid such as acetic acid. If desired, the hydrolysis can generally be conducted in situ. The acid treatment affords an economic advantage, and in some instances also produces a cleaner (purer) acylation reaction product than is obtained by direct acylation of the salt (I). An economic advantage is afforded because the acid (e.g., acetic acid) is substantially less expensive than the acyl halide (C). Thus, where the salt (I) is acylated directly, two mols of acyl halide is stoichiometrically required per mol of salt (I).

By first hydrolyzing the salt (I), one of these acyi halide mols. is replaced with a less expensive mol of acid.

In the second step of the process, the salt of formula I or its acid is contacted with the appropriate acyl chloride of formula C under reactive conditions preferably in an inert organic solvent and optionally in the presence of an organic scavenger base, under reactive conditions. We have found that this process step affords very high yields of the product of formula 11. The acylated product of formula II further performs better in the cyclizing reaction (step 3) than does the corresponding secondary amine; probably due to the protection of the free NH with an acyl group. The product is generally a mixture of the 1-carboxy acid, and its anhydride (i.e.,

depending upon the relative mol ratio of reactants.

This process is typically conducted at temperatures in the range of about from 0 to 1 200C for about from 1 to 8 hours where a scavenger base is used. Lower temperatures are preferably used typically about from 0 to 250C. Where a scavenger base is not used then higher temperatures are used, typically about from 80 to 1 200C, to drive off the hydrogen chloride byproduct as a gas.

Generally, about from 2 to 2.5 mol, preferably about from 2 to 2.2 mol of acyl chloride (C) is used per mol of reactant I (salt) and about half this amount of acyl halide when the acid formula I is used (i.e., about from 1.0 to 1.5, preferably about from 1.0 to 1.10 mol of acyl chloride per mol of I acid).

Suitable inert organic solvents which can be used include, for example, chlorinated hydrocarbons, e.g., methylene chloride, ethyl acetate, dimethoxymethane, benzene dioxane, tetrahydrofuran and the like and compatible mixtures thereof. Where the reaction is conducted in the presence of an organic scavenger base, to react with the hydrogen chloride byproduct, suitable scavenger bases which can be used include, for example, triethylamine, pyridine, 2,6-lutidine, sodium carbonate and the like.

The acyl chlorides and bromides (C) are known compounds and can be prepared by known procedures or obvious modifications thereof (e.g., substitution of appropriate substrates, solvents, etc.).

Generally, it is preferred to use acyl chlorides.

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

Typically, this process is conducted at temperatures in the range of about from 0 to reflux, preferably above about 50C for about from 1/4 hour to 2 hours preferably about from 1/4 to 1 hour.

Generally, about from 1 to 5 mols, preferably about from 2 to 2.5 mols of reactant II are used per mol of cyclizing agent. Optimum temperatures and ratios of cyclizing agents will vary with the particular cyclizing agent, for example, where sulfuric acid is used as the cyclizing agent only a relatively small amount is preferably used. Where, for example, phosphorus trichloride is used as the cyclizing agent, it is preferred to use about from 2 to 2.5 mols of reactant II per mol of phosphorus trichloride.

Also, since water is formed as a byproduct, it is preferred to conduct the reaction under conditions which remove water from the reaction system, for example, by distillation or the use of cyclizing reagents, etc. which combine with water.

Suitable inert organic solvents which can be used include, for example, chlorinated hydrocarbons, e.g., methylene chloride, ethyl acetate, benzene, dialkyl glycols, e.g., 1 ,2-dimethoxyethane, and the like and compatible mixtures thereof. Typically, a solvent ratio of about from 0.5 to 3 mols of reactant Il per liter of solvent is used.

A very broad range of cyclizing agents can be used. These reagents can be defined as reagents which will effect the esterification of a saturated fatty carboxylic acid upon contact of the acid with a low molecular weight primary alcohol. Suitable cyclizing agents which can be used, include, for example, carboxylic acid anhydrides, e.g. acetic anhydride, phthalic anhydride, acyl chlorides, e.g.

acetyl chloride, benzoyl chloride; trichloroacetic acid; p-toluene sulfonic acid; monoalkyl dehydrogen phosphites; e.g. decyl dihydrogen phosphite; boron trifluoride etherate; sulfonic acid type ion exchange resins; phosphorus trichloride, phosphorus tribromode, phosphoric acid, thionyl chloride, phosphorus pentachloride, sulfuric acid, phosgene, oxalyl chloride, carboxylic acids and the like, and compatible mixtures thereof.

Very good results are obtained by conducting the process using about from 2 to 2.5 mol of reactant Il per mol of phosphorus trichloride in methylene chloride at temperatures in the range of about from 5 to 1 50C. Good results are also obtained by using acetic acid with a small amount of sulfuric acid as the cyclizing agent at reflux.

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

wherein Ar and R1 are as defined hereinabove.

Steps (2a) and (3a) can be effected in the same manner as described hereinabove with respect to steps (3) and (2), respectively. Also, as in the case of step (2), it is preferred to use the acid form of formula I as the starting material for step (2a) rather than the salt form.

In each of the above process steps, unless otherwise specified, it is preferred to separate the respective products of formulas I and II before conducting the next process step. Also, with the exception of the hydrolysis of the salt (I) to its acid, it is generally preferred to conduct the present process under substantially anhydrous conditions. The respective products of formulas I, II, Ila, and Ill can be separated from the respective product reaction mixtures by any suitable purification procedure such as, for example, evaporation, extraction, crystallizations, chromatography, distillation and the like.

Specific illustrations of suitable separation and purification procedures are illustrated in the examples set forth hereinbelow; however, it should be appreciated that other suitable procedures could also be used.

It should also be appreciated that where typical reaction conditions (e.g., temperatures, mol ratios, reaction times, etc.) have been given, that conditions both above and below these ranges can also be used, though generally less conveniently or with poor economics. Also, optimum reaction conditions (e.g., temperatures, solvents, reaction times) can vary with the particular reactants, concentrations, etc., used but can be obtained by routine experimentation.

Definitions As used herein, the following terms have the following meanings, unless expressly stated to the contrary.

The term "halo" refers to the group of fluoro, chloro, bromo and iodo.

The term "alkyl" refers to both straight- and branched-chain alkyl groups. The term "lower alkyl" refers to both straight- and branched-chain alkyl groups having a total from one through six carbon atoms and includes primary, secondary and tertiary alkyl groups. Typical lower alkyls include, for example, methyl, ethyl, n-propyi, isopropyl, n-butyl, t-butyl, n-hexyl and the like.

The term "alkoxy" refers to the radical R'O-- wherein R' is alkyl.

The term "lower alkoxy" refers to alkoxy groups having from one through six carbon atoms and includes, for example, methoxy, ethoxy, t-butoxy, hexoxy and the like.

The term "lower epoxyalkyl" refers to epoxyalkyl groups having from two through six carbon atoms including one or two epoxy groups. Such groups include, for example, 1,2-epoxypropyl (i.e.,

2,4-epoxypentyl (i.e., 4'-methyloxetanylmethyl;

1 2,4,5-diepoxyhexyl (i.e.

and the like.

The term "hydroxy lower alkyl" refers to the group having the formula HOR' wherein R' is lower alkyl and includes, for example, hydroxymethyl, 3-hydroxypentyl, 2-hydroxyethyl and the like.

The term "iower alkoxyalkyl" refers to the radical R'OR"-- wherein R'O is lower alkoxy and R" is lower alkyl.

The term "lower alkylthioalkyl" refers to the radical R'SR"-- wherein R' and R" are independently lower alkyl. Typical lower alkylthioalkyl groups include, for example, methylthiomethyl, 4-t-butylthiohexyl.

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

The term "lower alkenyl" refers to alkenyl groups having two through six carbon atoms. Typical lower alkenyl groups include, for example, allyl, but-3-enyl, 2-methylpent-4-enyl and the like.

The term "lower alkenyloxy" refers to groups having the formula R50-- wherein R5 is lower alkenyl.

The term "lower alkenyloxyalkyl" refers to groups having the formula R50R'-- wherein R5 is lower alkenyl and R' is lower alkyl. Typical lower alkenyloxyalkyl groups include, for example, allyloxymethyl; 2-(but-3-enyloxy)hexyl; and the like.

The term "aryl" refers to aryl groups having six through twelve carbon atoms and includes, for example, phenyl and naphthyl.

The term "phenoxy-lower alkyl" refers to groups having the formula Ph-O-F'- wherein Ph is phenyl and R' is lower alkyl and includes, for example, phenoxymethyl, phenoxyhexyl, 5-phenoxy-3- methylpentyl and the like.

The term "phenylthio-lower alkyl" refers to groups having the formula Ph-S-F'-wherein Ph is phenyl and R' is lower alkyl and includes, for example, phenylthiomethyl, phenylthioethyl, 4-phenylthio- 1-methylbutyl- and the like.

The term "substituted phenoxy-lower alkyl" refers to groups having the formula Ph'-O-F'- wherein R' is lower alkyl and Ph' is a phenyl group having one or two substituents independently selected from the group of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy. Typical substituted phenoxy-lower alkyl groups include, for example, 44luorophenoxymethyl; 2-iodo-5 bromophenoxymethyl; 2-(2,5-dimethylphenoxy)ethyl; 4-(2-methoxy-4-chlorophenoxy)-1 -methylbutyl) and the like.

The term "substituted phenylthio-lower alkyl" refers to groups having the formula Ph'-S-F'- wherein R' is lower alkyl and Ph' is a phenyl group having one or two substituents independently selected from the group of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy. Typical substituted phenylthio-lower alkyl groups include, for example, 4-fluorophenylthiomethyl; 2-iodo-5bromophenylthiomethyl; 2-(2,5-dimethylphenylthio)ethyl; 4-(2-hexoxy-4-chlorophenylthio)-1- methylbutyl and the like.

The term "unsubstituted fatty acid" refers to carboxylic acids having the formula R'COOH wherein R' is an alkyl group having from 1 through 20 carbon atoms.

The term "low molecular weight primary alcohol" refers to a primary alcohol having a molecular weight below about 70, such as for example methanol, ethanol, and the like.

Utility As before mentioned, the products of formula Ill are useful for controlling fungi, particularly plant fungal infections; see Belgium Patent No. 871,668. For example, the compounds have been applied as fungicides against fungal diseases such as downy mildews, e.g., Plasmopara viticola (grapes) and Peronospora parasitica (cabbage and collard), late blights, e.g., Phytophthora infestans (tomatoes and potatoes), and crown and root rots, e.g., Phytophthora.

These compounds are particularly useful fungicides because they cure certain types of established fungal infections. This permits economical use of the fungicides of the invention, because they need not be applied to plants unless fungal infection actually occurs. Thus, a preventative program of applying fungicides against potential fungal infection is not necessary.

When used as fungicides, the compounds are applied in fungicidally effective amounts to fungi and/or their habitats, such as vegetative hosts and nonvegetative hosts, e.g., animal products. The amount used will, of course, depend on several 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 full strength, but are generally incorporated with conventional, biologically inert extenders or carriers normally employed for facilitating dispersion of active fungicidal compounds, recognizing that the formulation and mode of application may affect the activity of the fungicide.Thus, the compounds may be so formulated and applied as granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as solutions, or as any of several other known types of formulations, depending on the desired mode of application.

Wettable powders are in the form of finally divided particles which disperse readily in water or other dispersant. These compositions normally contain from about 580% fungicide, and the rest inert material, which includes dispersing agents, emulsifying agents and wetting agents. The powder may be applied to the soil as a dry dust or preferably as a suspension in water. Typical carriers include fuller's earth, kaolin clays, silicas, and other highly absorbent, wettable, inorganic diluents.Typical wetting, dispersing or emulsifying agents include, for example: the aryl and alkylaryl sulfonates and their sodium salts, alkylamide sulfonates, including fatty methyl taurides; alkylaryl polether alcohols, sulfated higher alcohols and polyvinyl alcohols; polyethylene oxides, sulfonated animal and vegetable oils; sulfonated petroleum oils, fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition products of long-chain mercaptans and ethylene oxide. Many other types of useful surface-active agents are available in commerce. The surface-active agent, when used, normally comprises from 1% to 1 5% by weight of the fungicidal composition.

Dusts are freely flowing admixtures 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 toxicant. 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 toxicant.

Useful liquid concentrates include the emulsifiable concentrates, which are homogeneous liquid or paste compositions which are readily dispersed in water or other dispersant, and may consist entirely of the fungicide with a liquid or solid emulsifying agent, or may also contain a liquid carrier such as xylene, heavy aromatic naphthas, isophorone, and other nonvolatile organic solvents. For application, these concentrates are dispersed in water or other liquid carrier, and are normally applied as a spray to the area to be treated.

Other useful formulations for fungicidal applications include simple solutions of the active fungicide in a dispersant in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalines, xylene, or other organic solvents. Granular formulations, wherein the fungicide is carried on relatively course particles, are of particular utility for aerial distribution or for penetration of cover-crop canopy. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low-boiling dispersant solvent carrier, such as the Freons, may also be used. All of those techniques for formulating and applying fungicides are well known in the art.

The optimum percentages by weight of the fungicide (active compound) may vary according to the manner in which the composition is to be applied and the particular type of formulation, but in general comprise 0.5 to 95% by weight of the fungicidal composition.

The fungicidal compositions may be formulated and applied with other active ingredients, including other fungicides, insecticides, nematocides, bactericides, plant growth regulators, fertilizers, etc.

A further understanding of the invention can be had from the following non-limiting examples.

Also, as used hereinabove and below, unless expressly stated to the contrary, all temperature ranges refer to the Celsius system and the term "ambient" or "room" temperature refers to about 200 C- 250C. The term percent (or "%" refers to weight percent, and the term "mol" or "mols" refers to gram mols. The term "equivalent" refers to an amount of reagent equal in mols to mols of the preceding or succeeding reactant recited in the preparation or example in terms of mols or finite weight or volume.

Also, unless expressly stated to the contrary, racemic mixtures and/or diastereomeric mixtures are used as starting materials, and correspondingly racemic mixtures and/or diastereomeric mixtures are obtained as products. Where necessary, examples are repeated to provide sufficient quantities of starting materials for subsequent preparations and examples. The abbreviation E.A. refers to elemental analysis, for both calculated and found values in weight percent.

Where given proton-magnetic resonance spectrum (p.m.r.) are determined at 60 mHz, and signals are assigned as singlets (s), broad singlets (bs), doublets (d), double doublets (dd), triplets (t), double triplets (dt), quartets (q) and multiplets (m).

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

In this example, 1 5 ml of anhydrous dimethoxyethane was admixed with 1.98 (0.022 mol) of 2methyl-2-propanthiol and 1.08 g (0.02 mol) of sodium methoxide. The mixture was refluxed for 1 hour, then cooled to room temperature and 4.10 g (0.02 mol) of 3-(2,6-dimethylphenylamino)-gammabutyrolactone was added. The resulting mixture was refluxed for 1-1/4 hours, then about 0.2 g of sodium methoxide was added and the refluxing continued for another hour. At the end of this time, the mixture was cooled and 20 ml of ice water was added. The mixture was then extracted with toluene and the remaining aqueous phase then acidified with glacial acetic acid to pH 6 and extracted with methylene chloride.The methylene chloride extract was then washed three times with water, dried over magnesium sulfate and evaporated affording 2.80 g of 1-carboxy-1-(2,6-dimethylphenylamino)3-t-butylthiopropane as a viscous oil.

Similarly, by following the same procedure but using the corresponding lactone starting materials in place of 3-(2,6-dimethylphenylamino)-gamma-butyrolactone, the following compounds are respectively prepared: 1 -carboxy-1 -(2,3,6-trimethylphenylamino)3-t-butylthiopropane; 1 -carboxy-1 -(2-methoxy-6-methylphenylamino)3-t-butylthiopropane; and 1 -carboxy- 1 -naphthylamino-3-t-butylthiopropane.

Similarly, by following the same procedure but in place of preparing the thiolate in situ, the thiolate salts potassium allylthiolate, ammonium benzylthiolate, and sodium naphthylthiolate are respectively reacted directly with each of the butyrolactone starting materials used above to yield the corresponding thioethylene, thiobenzene, and thionaphthylene analogs of each of the above products.

Example 2 This example illustrates the second step of the present process.

In this example 1.1 g (0.0037 mol) of 1-carboxy-1-(2,6-dimethylphenylamino)-3-t-butylthiopropane was dissolved in 10 ml of methylene chloride containing 0.56 g (0.0554 mol) of triethylamine. The mixture was cooled to OOC and 0.44 g (0.0041 mol) of methoxyacetyl chloride was dropwise admixed therewith and the resulting mixture stirred at OOC for 10 minutes. The mixture was then warmed to room temperature for 30 minutes and then poured into ice water.The methylene chloride phase was extracted, washed once with aqueous hydrochloric acid, twice with water, and then dried over magnesium sulfate and evaporated affording 1.3 g of 1-carboxy-1-[N-(2,6-dimethyl- phenyl)-methoxyacetamido]-3-t-butylthiopropane, containing a small amount of 1-methoxyacetyloxy- carbonyl derivative as an oil. The conversion obtained for this step based on the carboxy starting material was about 95%.

Similarly, by following the same procedure but respectively using each of the products of Example 1 as starting materials, the corresponding methoxyacetamido derivatives of formula (II) are respectively prepared.

Similarly, by following the same procedure but respectively replacing methoxyacetyl chloride with chloroacetyl chloride, cyclopropyl carbonyl chloride, benzoyl chloride and 2,3-epoxybutyryl chloride, corresponding chloroacetamido, cyclopropylamido, benzoylamido and 2,3-epoxybutyramido analogs of each of the above compounds are respectively prepared.

Example 3 This example illustrates the third step of the present process.

In this example, 1.7 g (0.0046 mol) of the 1-carboxy-1-[N-(2,6-dimethylphenyl)-N- methoxyacetamido]-3-t-butylthiopropane product prepared according to Example 2 hereinabove was dissolved in 10 ml of anhydrous methylene chloride. The mixture was then cooled to OOC and 0.317 g (0.0023 mol) of phosphorous trichloride was admixed therewith. The mixture was stirred at OOC 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 was then decanted to eliminate a small amount of solids precipitate which had formed. The methylene chloride phase was then removed and washed sequentially with water, 5% weight aqueous sodium carbonate, twice with water, 1 N. aqueous hydrochloric acid then twice more with water.The washed mixture was then dried over magnesium sulfate and evaporated affording 1.0 g of 3-(N-methoxyacetyl-N-2,6-dimethylphenylamino)-gammabutyrothiolactone as a oil. The oil was then crystallized from isopropyl alcohol. The infrared spectra and proton magnetic resonance spectra of the crystalline product was obtained and was found to be identical to the spectra of a control sample of 3-(N-methoxyacetyl-N-2,6-dimethylphenylamino)gamma-butyrothiolactone.

Similarly, by following the same procedure but using the corresponding products of Example 2 as starting materials the corresponding butyrothiolactone derivatives are respectively prepared.

Example 3A This example illustrates the third step of the present process using a different cyclizing agent than used in Example 3.

In this example, a solution containing 0.24 g of sulfuric acid, 4 ml of toiuene and 6 ml of acetic acid were added to 2.35 m mol of 1-carboxyl-1-[N-(2,6-dimethylphenyl)-N-methoxyacetamido]-3-t- butylthiopropane. The mixture was then heated at reflux (about 1 00C) for 2 hours and then cooled and washed twice with 10 ml of water. (A small amount of methylene chloride was added to prevent solids from precipitating out during washing). The washed mixture was then evaporated to dryness at 500C affording 3.65 g of 3-(N-methoxy-acetyl-N-2,6-dimethylphenylamino)-gamma- butyrothiolactone as a solid. The water washings were combined and extracted with methylene chloride.The methylene chloride extract was evaporated to dryness affording an additional 0.27 g of 3 (N-methoxyacetyl)-N-2,6-dimethylphenylamino)-gamma-butyrothiolactone as a solid.

Similarly, by following the same procedure but using the corresponding products of Example 2 as starting materials, the corresponding butyrothiolactone derivatives are respectively prepared.

Example 4 Examples 4-6 illustrate the present process wherein the salt (I) is directly acylated without prior conversion to the acid.

In this example, 9.5 g (0.1 mol) of 2-methyl-2-propanthiol was added to a stirred slurry containing 6 of sodium methoxide (0.1 mol) in 70 ml of anhydrous 1,2-dimethoxyethane at room temperature. The resulting mixture was stirred at room temperature for about 30 minutes (resulting in the production of sodium 2-methyl-2-propanethiolate) and then 20.5 g (0.1 mol) of 3-(2,6-dimethylphenylamino)-gamma-butyrolactone was added. The mixture was then heated at reflux until the slurry became a clear solution (about one hour). The solution was evaporated to remove solvent and byproduct methanol affording sodium 1 -(2,6-dimethylphenylamino)- 1 -(2-t-butylthioethyl) acetate (I) as a residue.

Similarly, by following the same procedure but using the corresponding 3-aryl or substituted arylamino-gamma-butyrolactone starting materials, the following compounds are respectively prepared; sodium 1 -(phenylamino)- 1 -(2-t-butylthioethyl) acetate; sodium 1-(4-fluorophenylamino)-1-(2-t-butylthioethyl) acetate; sodium 1 -(2-iodophenylamino)- 1 -(2-t-butylthioethyl) acetate; sodium 1 -(2,6-dichlorophenylamino)- 1 -(2-t-butylthioethyl) acetate; sodium 1 -(2-methoxyphenylamino)-1 -(2-t-butylthioethyl) acetate; sodium 1 -(2-methyl-4-pentylphenylamino)- 1 -(2-t-butylthioethyl) acetate; sodium 1 -(2,6-dibromophenylamino)- 1 -(2-t-butylthioethyl) acetate;; sodium 1 -(2-methyl-3-chlorophenylamino)- 1 -(2-t-butylthioethyl) acetate; Similarly, by following the same procedure but respectively replacing the in situ prepared sodium 2-methyl-2-propanethiolate with potassium hex-4-enylthiolate, calcium di(methylthiolate) and ammonium benzylthiolate, the corresponding analog salts of each of the above products are respectively prepared.

Example 5 In this example, the sodium 1 -(2,6-dimethylphenylamino)- 1 -(2-t-butylthioethyl) acetate (I) residue from Example 4, was redissolved in 250 ml of dimethoxyethane and heated to reflux. 7.5 g (0.1 mol) of N,N-dimethylformamide was then added followed by the addition of 9.5 g (0.1 mols) of acryloyl chloride at which time the solution became light brown. The mixture was cooled to room temperature and another 7.5 g (0.1 mol) of N,N-dimethylformamide was then added followed by the addition of another 9.5 g (0.1 mols) of acryloyl chloride. The mixture was then refluxed for 1-1/2 hours and then evaporated under vacuum to remove solvent.The residue was slurried with diethyl ether, filtered over diatomaceous earth and evaporated affording acrylic-1 -[N-(2,6-dimethylphenyl)-N-acryloylamino]-1 - (2-t-butylthioethyl) acetic acid anhydride as the residue.

Similarly, by following the same procedure using the corresponding products of Example 4 as starting materials, the following compounds are respectively prepared: acrylic-1 (N-phenyl-N-acryloyla mino)-l -(2-t-butylthioethyl acetic acid anhydride; acrylic-1 -[N-(4-fluorophenyl)-N-acryloylaminoj-2-t-butylthioethyl acetic acid anhydride; acrylic-i -[N-(2,6-dichlorophenyl)-N-acryloylamino]-2-t-butylthioethyl acetic acid anhydride; acrylic-i -[N-(2-methoxyphenyl )-N-acryloylamino]-2-t-butylthioethyl acetic acid anhydride; acrylic-1 -[N-(2-methyl-4-pentyiphenyl)-N-acryloyla mino]-2-t-butylthioethyl acetic acid anhydride; acrylic-1 -[N-(2,6-dibromophenyl)-N-acryloylaminoj-2-t-butylthioethyl acetic acid anhydride; and acrylic-l -[N-(2-methyl-3-chlorophenyl)-N-acryloylaminoj-2-t-butylthioethyl acetic acid anhydride.

Similarly, by following the same procedure but in place of acryloyl respectively using acetyl chloride; dichloroacetyl chloride; hydroxyacetyl chloride; methoxyacetyl chloride; methylthioacetyl chloride; phenylthioacetyl; phenoxyacetyl; 2,6-dimethylphenylacetyl chloride; 4-ethoxyphenylacetyl chloride and 2,3-epoxybutyryl chloride the corresponding diacyl derivatives of each of the above compounds are respectively prepared, for example:: acetic- 1 -[N-(2,6-dimethylphenyl)-acetamido]-2-t-butylthioethyl acetic acid anhydride; dichloroacetic-1-(N-phenyl-dichloroacetamido)-2-t-butylthioethyl acetic acid anhydride; hydroxyacetic- 1 -[N-(4-fluornphenyl)-hydrnxyacetamido]-2-t-bulthioethyl acetic acid anhydride; methoxyacetic- 1 -[N-(2,6-dimethylphenyl)-methoxyaceta mido]-2-t-butylthioethyl acetic acid anhydride; methylthioacetic- 1 -[N-(2,6-dichlorophenyl)-methylthioaceta mido]-2-t-butylthioethyl acetic acid anhydride; phenylthioacetic- 1 -[N-(2-methoxyphenyl)-phenylthioacetamido]-2-t-butylthioethyl acetic acid anhydride; phenoxyacetic- 1 -[N-(2-methyl-4-pentylphenyl)-phenoxyacetam ido]-2-t-butylthioethyl acetic acid anhydride;; (2,6-dimethylphenyl)acetic-1 -[N-(2,6-dibromophenyl)-(2,6-dimethylphenyl)acetamidoj-2-t- butylthioethyl acetic acid anhydride; (4-ethoxyphenyl)acetic- 1 -[N-(2-methyl-3-chlorophenyl)-(4-ethoxyphenyl)aceta mido]-2-tbutylthioethyl acetic acid anhydride; 2,3-epoxybutyric- 1 -[N-(2,6-dimethylphenyl)-2,3-epoxybutyra mide] 2-t-butylthioethyl acetic anhydride, etc.

Example 6 In this example, the 1-acrylic-i [N(2,6-dimethylphenyl)-N-acryloylaminoj-2-t-buWlthioethyl acetic acid anhydride residue from Example 5, was mixed with 200 ml of dimethoxyethane and then 42 g (0.3 mol) of phosphorous chloride was slowly added. The resulting mixture was cooled to about 80C and then stirred at room temperature overnight (about 1 2 hours!. Thin layer chromographic analysis of a small sample of this showed the presence of some unreacted starting materials (i.e., the butylthiopropane derivative) and two other products. The reaction mixture was then heated at reflux for 24 hours and then evaporated to remove solvent.The residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate to neutralize acidic components and then washed with water and dried over magnesium sulfate. The methylene chloride was then removed by evaporation affording an oily residue. The oily residue was then chromatographed over 250 g of silica gel sequentially eluting 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 was then further eluted with 50% petroleum ether and ethyl ether affording about 3 g of 3-(N-acryloyl-N-2,6-phenylamino)gamma-butyrothiolactone.

Similarly, by following the same procedure, the products of Example 5 are respectively converted to the corresponding gamma-butyrothiolactone derivatives, for example: 3-(N-acryloyl-N-2,6-dichlorophenylamino)-gamma-butyrothiolactone; 3-[N-acryloyl-N-(2-methyl-3-chlorophenyl)-amino]-gamma-butyrothiolactone.

3-(N-dichloroacetyl-N-phenylamino)-gamma-butyrothiolactone; 3-(N-methoxyacetyl-N-2',6'-dimethylphenylamino)-gamma-butyrothiolactone; 3-(N-phenylthioacetyl-N-2'-methoxyphenylamino)-gamma-butyrothiolactone; 3-[N-(2,6-dimethylphenyl)acetyl]-N-(2,6-dibromophenyl)-amino]-gamma-butyrothiolactone; 3-[N-(2,3-epoxybutyryl)-N-(2,6-dimethylphenyl)am ino]-ga m ma-butyrothiolactone; etc.

Example 7 In this example, the procedures of Examples 2 and 5 are repeated but using the corresponding acyl bromides in place of the acyl chloride. Samples of the resulting products of formula II are then respectively converted to the corresponding compounds of formula Ill by applying the procedure of Example 3 and the procedures of Example 3A.

Example 8 This example illustrates the alternative process mode of this invention.

A. A solution of 3-(N-2,6-dimethylphenylamino)-gamma-butyrolactone (11 .89 g.) in dimethoxy ethane was added to 6.5 g. sodium t-butylmercaptide. The solution was refluxed for four hours and stripped. The residue was dissolved in water, acidified with hydrochloric acid and extracted with methylene chloride. The organic phase was collected, dried (MgSO4) and stripped to yield 1 5.2 g.

viscous oil (IR spectrum shows presence of-CO2H).

B. A 5 g. portion of the oil was stirred in 10 ml. (15.7 g.) phosphorus trichloride at room temperature for two days. The excess phosphorus trichloride was stripped at 600C and the residue was dissolved in methylene chloride, 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-gamma-butyrothiolactone (Yield 34.8%).

C. The product of step B is then acylated via the procedure described in Example 2 hereinabove affording 3-(N-methoxyacetyl-N-2,6-dimethylphenylamino)-gamma-butyrothiolactone.

Obviously, many modifications and variations of the invention, described hereinabove and below in the claims, can be made without departing from the essence and scope thereof.

Claims

1. A process for preparing a 3-(N-aryl-N-acylamino)-gamma thiobutyrolactone represented by the general formula:

wherein Ar is aryl or substituted aryl having from one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy; R' is lower alkyl, lower alkoxy, cycloalkyl having three to six carbon atoms, lower epoxy-alkyl, lower alkenyl, lower alkenyloxy, hydroxymethyl, haloalkyl having one to three halo substituents and one to six carbon atoms; lower alkoxyalkyl, lower alkylthioalkyl, phenylthio-lower alkyl, phenoxy-lower alkyl, phenylthio-lower alkyl or substituted phenoxy-lower alkyl having one or two ring substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy; and R2 is hydrogen, chloro, bromo, lower alkyl, phenyl, or substituted phenyl having one or two ring substituents independently selected from the group consisting of fluoro, chloro, bromo and lower alkyl; which process comprises the steps of: (a) contacting the corresponding arylamino-gamma-butyrolactone having the general formula:

wherein Ar and R2 are as defined hereinabove, with a thiolate salt under reactive conditions to form the corresponding 1 -(Ar-amino)-3-thiopropane 1 -ca rboxylate sait; (b) contacting under reactive conditions said 1-(Ar-amino)-3-thiopropane 1-carboxylate salt with an acyl halide having the general formula:

wherein R1 is as defined hereinabove and X is chloro or bromo; and (c) contacting under reactive conditions the N-acylamino product of step (b) with a cyclizing agent, which will effect esterification of a saturated carboxylic fatty acid upon contact with a low molecular weight primary alcohol, to form the required corresponding compound of formula Ill, or optionally conducting step (c) prior to step (b) to yield the corresponding thiolactone intermediate and acylating said thiolactone intermediate according to step (b) to yield the corresponding compound of formula Ill.

2. A process according to Claim 1, wherein the compound of formula (A) is 3-(2,6dimethylphenylamino)-gamma-butyrolactone.

3. A process according to Claim 1 or 2, wherein said thiolate salt is an alkali metal thiolate.

4. A process according to Claim 3, wherein said thiolate salt is sodium 2-methyl-2propanethiolate.

5. A process according to Claim 1, wherein said thiolate salt has the formula MSR and the product of step (b) has the general formula:

wherein Ar, R1 and R2 are as defined in Claim 1; M is an inorganic cation, R is lower alkyl, lower alkenyl or aryl-lower alkyl and R3 is H or the radical

wherein R' is selected from the same group of substituents as R1.

6. A process according to any preceding claim, wherein said step (b) is conducted at a temperature in the range from OOC to 1 200C.

7. A process according to any preceding claim, wherein said step (a) is conducted in an inert organic liquid.

8. A process according to any preceding claim, wherein said step (b) is conducted in an inert organic solvent.

9. A process according to any preceding claim, wherein said step (c) is conducted in an inert organic solvent.

10. A process according to any preceding claim, wherein said 1 -(aryl-amino)-3-thiopropane carboxylate salt is contacted with from 2 to 2.2 mols of said acyl halide per mol of said salt in said step (b).

11. A modification of the process claimed in Claim 1, which comprises the steps of: (a) contacting the corresponding arylamino-gamma-butyrolactone having the general formula:

wherein Ar and R2 are as defined in Claim 1 , with a thiolate salt under reactive conditions to form the corresponding 1 -(aryl-amino)-3-thiopropane 1-carboxylate salt; (b) contacting under reactive conditions said carboxylate salt with an acid to form the corresponding 1 -(a rylamino)- 1 -carboxy-3-thiopropane; (c) contacting said 1-(aryl-amino)-1-carboxy-3-thiopropane with an acyl halide having the general formula:

wherein R' is as defined in Claim 1 and X is chloro or bromo; and (d) contacting under reactive conditions the N-acylamino product of step (c) with a cyclizing agent, capable of converting carboxylic acids or esters to acid halides, to form the corresponding compound of formula Ill.

12. A process according to Claim 11, wherein the compound of formula (A) is 3-(2,6 dimethylphenylamino)-gamma-butyrolactone

13. A process according to Claim 11 or 12, wherein said thiolate salt is an alkali metal thiolate.

14. A process according to Claim 13, wherein said thiolate salt is sodium 2-methyl-2propanethiolate.

1 5. A process according to Claim 11, 12, 13 or 14, wherein said step (c) is conducted at a temperature in the range from OOC to 1 200C.

1 6. A process according to any one of Claims 11 to 1 5, wherein said step (a) is conducted in an inert organic liquid.

17. A process according to any one of Claims 11 to 16, wherein said step (c) is conducted in an inert organic solvent.

18. A process according to any one of Claims 11 to 17, wherein said step (d) is conducted in an inert organic solvent.

19. A process according to any one of Claim 11 to 18, wherein in said step (c) said 1 -(arylamino) 1 -carboxy-3-thiopropane is treated with from 1 to 1.1 mols of said acyl halide per mol of said 1 (arylamino)-carboxy-3-thiopropane.

20. A process according to Claim 1, which comprises the steps of: (a) contacting an arylaminolactone having the general formula:

wherein Ar and R2 are as defined in Claim 1, with a thiolate salt having the formula: MSR wherein M is an alkali metal cation and R is lower alkyl, lower alkenyl, or aryl-lower alkyl, in an inert organic liquid carrier under reactive conditions at a temperature in the range from 20 to 2000C to form the corresponding compound having the general formula:

wherein Ar, M, R and R2 are as defined hereinabove; (b) contacting the compound of formula (I) with an acyl halide having the general formula:

wherein R' is as defined in Claim 1 and X is chloro or bromo; in an inert organic solvent under reactive conditions at a temperature in the range from 0 to 1 200C to form the corresponding acylated product selected from the group represented by the general formulae:

wherein Ar, R1, R2 and R are as defined hereinabove; and (c) contacting the acylated product of step (b) with a cyclizing condensing agent selected from the group of compounds which will effect esterification of a saturated fatty acid with a low molecular weight primary alcohol, in an inert organic solvent under reactive conditions to form the corresponding compound of formula lil.

21. A process according to Claim 20, wherein said inert organic liquid of step (a) is selected from 1 ,2-dimethoxyethane, diglyme, and mixtures thereof and said inert organic solvents of steps (b) and (c) are independently selected from glacial acetic acid, dichloromethane, 1 ,2-dichloroethane, toluene, and mixtures of two or more thereof.

22. A modification of the process claimed in Claim 20, which comprises the steps of: (a) contacting an arylaminolactone having the general formula:

wherein Ar and R2 are as defined in Claim 1, with a thiolate salt having the formula: MSR wherein M is an alkali metal cation and R is lower alkyl, lower alkenyl, or aryl-lower alkyl, in an inert organic liquid carrier under reactive conditions at a temperature in the range from 20 to 2000C to form the corresponding compound having the general formula::

wherein Ar, M, R and R2 are as defined hereinabove; (b) contacting said compound of formula (I) with an acid under reactive conditions to form the corresponding 1 -arylamino-1 -carboxy-3-thiopropane; (c) contacting the said 1-arylamino-1-carboxy-3-thiopropane with an acyl halide having the general formula:

wherein R1 is as defined hereinabove and X is chloro or bromo; in an inert organic solvent under reactive conditions at a temperature in the range from 0 to 1 200C to form the corresponding acylated product selected from the group represented by the general formulae:

wherein Ar, R', R2 and R are as defined hereinabove; and (d) contacting the acylated product of step (c) with a cyclizing agent selected from the group of compounds which will effect esterification of a saturated fatty acid with a low molecular weight primary alcohol, in an inert organic solvent under reactive conditions to form the corresponding compound of formula Ill.

23. A process according to Claim 22, wherein said inert organic liquid of step (a) is selected from 1 ,2-dimethoxyethane, diglyme, and mixtures thereof and said inert organic solvents of steps (b) and (c) are independently selected from glacial acetic acid, dichioromethane,1,2-dichloroethane, toluene, and mixtures of two or more thereof.

24. A process according to Claim 22 or 23, wherein said cyclizing condensing agent is selected from phosphorus trichloride and mixtures of glacial acetic acid containing a minor amount of sulfuric acid.

25. A process according to Claim 24, wherein said inert organic liquid of step (a) is 1,2dimethoxyethane and said inert organic solvents of step (b) and step (c) are each methylene chloride.

26. A process according to Claim 23, wherein R2 is hydrogen.

27. A process according to Claim 25, wherein said starting material of formula A is (2,6dimethylphenylamino)-gamma-butyrothiolactone and said acyl halide is methoxyacetyl chloride and said product of formula Ill has the formula:

28. A process according to Claim 22 or 26, wherein said thiolate salt is an alkali metal thiolate.

29. A process according to Claim 22 or 27, wherein said thiolate salt is sodium 2-methyl-2propanethiolate.

30. Compounds represented by the general formula:

wherein Ar is aryl or substituted aryl having from one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy; R is lower alkyl, lower alkenyl, or aryl-lower alkyl; R' is lower alkyl, lower alkoxy, cycloalkyl having three to six carbon atoms, lower epoxyalkyl, lower alkenyl, lower alkenyloxy, hydroxymethyl; haloalkyl having one to three halo substituents and from one to six carbon atoms; lower alkoxyalkyl, lower alkylthioalkyl, phenylthiolower alkyl, phenoxylower alkyl, phenyl-lower alkyl or substituted phenoxy-lower alkyl or phenylthio-lower alkyl having one or two ring substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl and lower alkoxy; R2 is hydrogen, chloro, bromo, iodo, lower alkyl, phenyl substituted phenyl having one or two ring substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, or lower alkyl; and R3 is hydrogen or the radical

wherein R1 is as defined hereinabove.

31. Compounds as claimed in Claim 30, wherein R is t-butyl, allyl, or benzyl.

32. A process for preparing a compound as claimed in Claim 30, which comprises contacting the corresponding compound represented by the general formula:

wherein Ar, R and R2 are as defined in Claim 30, M1 is hydrogen or a cation, and m' is the valence of M1; with an acyl halide having the general formula:

wherein X is chloro or bromo and R1 is as defined in Claim 30, under reactive conditions to form the required corresponding compound of Claim 30.

33. A proces for preparing a compound having the general formula:

wherein Ar and R2 are as defined in Claim 1; comprising the steps of: (a) reacting a compound having the general formula:

wherein Ar and R2 are as defined hereinabove, with a thiolate salt under reactive conditions, and (b) reacting the product produced in step (a) with a reagent capable of effecting esterification of a saturated carboxylic fatty acid upon contact with a low molecular weight primary alcohol to form the required compound of formula (I).

34. A process according to Claim 33, wherein the product of step (a) is converted to the acid prior to step (b).

35. A process according to Claim 34, wherein said thiolate salt is 2-methyl-2-propanethiolate and said reagent of step (b) is phosphorus trichloride.

36. A process according to Claim 35, wherein Ar is 2,6-dimethylphenyl.

37. A process substantially as described in any one of the foregoing Examples.