FIELD OF THE INVENTION The present invention relates to processes for the preparation of endosulfan. In particular, the invention relates to a process for the preparation of endosulfan enriched in the (3-isomer thereof ( (3-endosulfan). The invention also provides a process for enriching the p-isomer content of a mixture of a-and ß-endosulfan, and to processes for obtaining p-endosulfan in substantially pure form.

BACKGROUND Endosulfan (6,7, 8,9, 10, 10-hexachloro-1, 5, 5a, 6,9, 9a-hexahydro-6,9-methano-2, 4,3- benzodioxathiepine-3-oxide) (1) is a broad spectrum organochlorine insecticide and acaricide with contact and stomach action, used on a variety of crops including vines, olives, tea, coffee, rice, sugar cane, tobacco, cereals, fruits, vegetables and cotton. It exists in two stereoisomeric forms: a-endosulfan (m. p. 109. 2°C) and (3-endosulfan (m. p.

213. 3°C) l.

The commercial preparation of endosulfan involves the reaction of 1,4, 5,6, 7,7-hexachloro- <BR> <BR> 2,3-bis (hydroxymethyl) -bicyclo [2: 2: 1] hept-5-ene (endosulfan diol) with thionyl chloride as depicted in Scheme (1) 2, 3. This process provides a final endosulfan product which has a predominance of the a-isomer, typically 65-75% and the commercial product is applied as a 7: 3 mixture of a- : (3-isomers.

Scheme 1 The a-and (3-forms of endosulfan are known to possess differing physical and chemical properties, with one form or the other showing a residual predominance in various environments, for example, the a-isomer is predominant in air and snow samples, while the (3-form is favoured in rain samples4.

It has recently been discovered 5 that p-endosulfan has similar levels of efficacy as a pesticide to that of a-endosulfan. However, the a-and (3-isomers do not contribute equally to environmental residue problems associated with endosulfan. After application, a- endosulfan dissipates by volatilisation or is oxidised on the surface of plants or in the soil to the toxic metabolite endosulfan sulfate. Endosulfan sulfate accumulates in the fat of animals and so is generally the only residue detected in"endosulfan-contaminated"animal products. In contrast, (3-endosulfan is more persistent on the plant surface and is more prone to hydrolysis to the non-toxic endosulfan diol than is the a-isomer. Thus, endosulfan formulations enriched in the (3-isomer have the potential to present a lower risk to the environment than the currently commercially employed 7: 3 mixture of a- : (3-isomers. It is therefore desirable to prepare endosulfan formulations which are enriched in the (3-isomer compared to the currently employed 7: 3 mixture ofa- : (3-isomers.

Previous attempts to separate the (3-isomer from the a-isomer have included fractional crystallisation, the product of which may be further recrystallised to afford substantially pure P-isomer, and chromatography. Such methods, however, are inefficient in preparing (3-endosulfan because of the small proportion of the 0-isomer present in the

original 7: 3 isomeric mixture and the need to dispose of a large amount of the remaining a- isomer.

Earlier studies have also examined the interconversion of the a-and (3-isomers (ie, isomerisation) by microbial means7 and irradiation with UV light8. Isomerization has also been achieved chemically by heating a 7: 3 mixture of a-and (3-isomers, under dilute (lmg/L) conditions, at 45°C in a 2: 3 mixture of toluene: acetone acidified with aqueous hydrochloric acid. This results in an endosulfan product having a 45: 55 ratio of a- : p- isomers. However, in this process, endosulfan diol and the cyclic ether are by-products of the isomerisation reaction7. The conversion between the two isomers has been postulated to be the result of hydrolysis or that assistance form water is necessary for the equilibrium to occur9. Other studies9 have demonstrated that the (3-isomer is readily converted to the a- isomer at 160°C but that no conversion of the a-isomer to the p-isomer occurred, even at temperatures up to 280°C. It was argued that since a-endosulfan is asymmetric and P- endosulfan is a symmetric molecule, the p-isomer must be converted to the a-form because of a net increase in entropy, whereas conversion of a-to p-endosulfan would require an increase in order.

A recently disclosedl° process for the stereoselective preparation of enriched p-endosulfan describes the use of a stereoisomer directing agent in an inert organic solvent at ambient to 139°C temperatures. The stereoisomer directing agent is the opposite isomer to that which is desired. Examples show that the selectivity of the process for P-endosulfan can reach >99% based on the amount of starting endosulfan diol. However, this process is limited by the large amount of a-stereoisomer directing agent (typically a 1.7 to 4.3 molar ratio) which is required to generate the (3-isomer. As a result, although the conversion of the starting endosulfan diol to the desired p-isomer may be achieved in nearly quantitative yields, the final isomeric mixture which contains a substantially higher proportion of a- isomer necessitates the separation of the minor (as a total of final endosulfan content) ß- isomer. WO 02085884 teaches that the stereoisomer directing agent may be separated from the mixture by fractional recrystallization as described in reference 6 mentioned above. Thus, in order to obtain substantially pure P-endosulfan in a practical and

economic process, the stereoisomers in this mixture must be separated, the p-isomer isolated and the a-isomer recycled. Furthermore, the efficiency based upon all inputs (stereoisomer directing agent and diol starting material) is less than 35% for the p-isomer.

None of the methods described above offer a practical means for obtaining an endosulfan mixture enriched in the p-isomer, or the p-isomer in substantially pure form, in commercial-type quantities, without the need for separation of the major unwanted a- isomer component or the substantial formation of by-products. There exists, therefore, a need for further processes for preparing endosulfan, enriched in the p-isomer, and substantially pure p-endosulfan. Such methods may advantageously be adapted to prepare p-endosulfan in commercial-type quantities.

SUMMARY OF THE INVENTION Throughout this specification and the claims which follow, unless the context requires otherwise, the word"comprise", and variations such as"comprises"and"comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

New processes have now been developed for preparing substantially pure p-endosulfan or endosulfan enriched in the p-isomer using a nucleophile under essentially anhydrous conditions.

Accordingly, the invention provides a process for enriching the p-endosulfan content of a mixture of a-and p-endosulfan comprising the step of treating the mixture with a nucleophile under substantially anhydrous conditions.

Optionally, the process may be carried out in the presence of an acid.

The resulting endosulfan product preferably comprises at least about 50-60% p-endosulfan.

By performing the process under substantially anhydrous conditions, it has also been found that isomerization of the a-isomer to the p-isomer can be carried out according to the invention such that the amount of endosulfan diol and cyclic ether by-products is reduced.

The conditions for the isomerization process may be applied to an existing endosulfan product, such as the commercially available 7: 3 mixture ofa- : p-isomcrs, or alternatively, may be incorporated into the process for synthesizing endosulfan from endosulfan diol such that the resulting reaction product is enriched in the (3-isomer. Thus by performing the synthesis of endosulfan in the presence of a nucleophile, under substantially anhydrous conditions, an endosulfan product enriched in the (3-isomer can be obtained.

Accordingly, the present invention also provides a method for preparing endosulfan enriched in the p-isomer comprising the step of reacting endosulfan diol with thionyl halide in the presence of a nucleophile under substantially anhydrous conditions.

In a further embodiment of the invention, the resulting obtained products, enriched in the 0-a-isomer, can be subjected to further fractional crystallisation to afford even further (3- isomer enriched endosulfan or preferably substantially pure p-endosulfan.

In yet another embodiment of the invention, the fractional crystallization process can be carried out simultaneously with the isomerization process in"one pot". In one potential commercial application of the processes described herein, the synthesis process for endosulfan can be coupled with a simultaneous isomerization/fractional crystallization process.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 schematically depicts a combination of the processes described herein which may be adaptable to commercial manufacture of (3-isomer enriched endosulfan or substantially pure endosulfan.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Throughout the specification"endosulfan"or"endosulfan product"refers to a mixture of the a-and (3-isomers of endosulfan. The terms"a-endosulfan"and"P-endosulfan"refer to the a-and p-isomers respectively.

Endosulfan enriched in the (3-isomer refers to a mixture of the a-and p-isomers which contains at least about 40%, more preferably 50% of the (3-isomer, and even more preferably at least about 60%. More preferred embodiments of the invention provide endosulfan containing the R-isomer in at least about 70 or 80%.

Substantially pure (3-endosulfan (or the (3-isomer) refers to endosulfan containing at least 90% (3-endosulfan, eg about 90% R-endosulfan and about 10% a-endosulfan, more preferably at least 95% R-endosulfan. Even more preferably, substantially pure ß- endosulfan refers to at least 96 or 97% p-endosulfan content and more preferably to at least 98 or 99% (3-endosulfan content.

As used herein, the term"substantially anhydrous"refers to conditions such that no significant amount of additional water is added (e. g. no more than about 5% or less, say about 2% or less, preferably about 1% or less, more preferably 0.5% or less, or 0.1% or less of total solvent or reaction volume). Preferably no additional water is added. For example, where acid is used, the acid is preferably not aqueous acid. However, it is not necessary to rigorously exclude water by drying reaction vessels, solvents/reagents etc.

As used herein, thionyl halide refers to thionyl chloride or bromide.

As used herein, the term"alkyl"denotes straight chain, branched or cyclic alkyl, preferably Cl 20 alkyl, eg Cl-lo or C16 Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2- dimethylpropyl, 1, 1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2, 2, -trimethylpropyl, 1,1, 2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4- dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2, 3- trimethylbutyl, 1,1, 2-trimethylbutyl, 1,1, 3-trimethylbutyl, octyl, 6-methylheptyl, 1- methylheptyl, 1,1, 3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-methyl-octyl, 1-, 2-, 3-, 4-or 5-ethylheptyl, 1-, 2-or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-and 8- methylnonyl, 1-, 2-, 3-, 4-, 5-or 6-ethyloctyl, 1-, 2-, 3-or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-ethylnonyl, 1-, 2-, 3-, 4-or 5- propylocytl, 1-, 2-or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5-or 6- propylnonyl, 1-, 2-, 3-or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono-or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.

Where an alkyl group is referred to generally as"propyl", butyl"etc, it will be understood that this can refer to any of straight, branched and cyclic isomers where appropriate.

The term"aryl"denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Particularly preferred aryl include phenyl and naphthyl, especially phenyl.

The term"aralkyl"refers to an alkyl group, substituted (preferably terminally) by an aryl group.

An"alkyl","aryl"or"aralkyl"group may be optionally substituted by one or more of carboxylic acid, carboxylic ester, amide, hydroxy, amino, alkyl amino, dialkylamino. An "alkyl"group may also optionally contain one or more double or triple bonds to form an alkenyl or alkynyl group.

The term"hetero-atom"includes oxygen, sulfur, nitrogen and phosphorous. The term "heterocyclic"includes a 3-, 4-, 5-, 6-, 7-or 8-membered carbocyclic group wherein one or more carbon atoms is replaced by a hetero-atom, each of which may be the same or different. A heterocyclic group may be saturated or unsaturated, aromatic or non-aromatic and can include pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, pyridinyl, imidazolyl, morpholino, indolinyl, imidazolinyl, pyrazolidinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, and tetrahydropyranyl.

Unless otherwise stated, the term"halogen" (or halide) refers to chlorine (chloro), fluorine (fluoro), bromine (bromo) or iodine (iodo).

It has now surprisingly been found that the presence of a nucleophile when synthesising endosulfan or isomerising the a-isomer under substantially anhydrous conditions, leads to a product enriched in the p-isomer.

Suitable nucleophiles are those which can act as both nucleophile and leaving group under the conditions of the process, thereby creating a reversible process. Examples of suitable nucleophiles include, without limitation, inorganic anions such as halide, (F-, Cl-, Br, I-) azide, nitrate and nitrite, preferably halide and most preferably chloride or bromide.

The nucleophile can be generated in situ from a nucleophilic source. Suitable nucleophilic sources are those which are soluble in the reaction medium and may include those having a tetravalent nitrogen atom such as quaternary ammonium salts, for example, ammonium salts of formula R4N+ where R may be any combination of H, alkyl, aralkyl or aryl, (preferably all R can not be H), such as tetramethyl (or ethyl or propyl or butyl) ammonium. Two or more R groups may also be joined to form a mono-or bicyclo-alkyl

or aralkyl amine. Other suitable nucleophilic sources include, without limitation, alkyl, aralkyl and heterocyclic immonium salts of formula R2N+=R'where R is H, alkyl, aralkyl or aryl and R'is alkyl or aralkyl. Alternatively, a nucleophilic source may be a salt formed from a heterocyclic nitrogen compound such as a pyridine, pyrimidine, quinoline, pyrrole or imidazole. Nucleophilic sources containing other hetero-atoms, such as sulphonium, phosphonium, oxonium or arsenium salts may also be used. The salt is preferably a halide salt (eg, Bi, Cl-, F-, or I-, particularly Br or Cl-). Preferred nucleophilic sources include quaternary ammonium salts, such as tetrabutyl ammonium chloride and bromide, and chloride and bromide salts of pyridine (such as methyl pyridinium chloride) guanidine, and tertiary amines such as triethylamine. A nucleophilic source may also be acid (eg, HC1 or HBr) and includes the acid generated in situ in the synthesis of endosulfan from endosulfan diol and thionyl halide. Particularly preferred nucleophilic sources include halogen acids, lithium halides, quaternary ammonium halides and tertiary amine hydrohalides.

It may be desirable to assist the dissociation of the nucleophilic source with a suitable dipolar organic compound. Suitable dipolar organic compounds are those molecules which are polarised, ie possess a dipole moment, and will promote dissociation of nucleophilic source. The dipolar compound must not react irreversibly with endosulfan under the conditions used. Thus, where the isomerization process takes place as a"one- pot"process with the synthesis of endosulfan, the dipolar organic compound must be thionyl halide compatible. It will be understood that suitable dipolar organic compounds must not be substantially decomposed under the reaction conditions and must be soluble or miscible in the reaction medium. Examples of dipolar organic compounds which may be suitable include, but are not limited to, nitriles (such as acetonitrile, benzonitrile, acrylonitrile and hydrogen cyanide), amides (such as dimethyl formamide, dimethyl acetamide, formamide, acetamide), N-alkyl pyrrolidones (including N-methyl pyrrolidone), fatty acid amides, ureas and alkyl ureas, sulphoxides (such as dimethyl sulphoxide), nitro compounds (such as nitromethane and nitrobenzene), phenols, esters (such as ethyl acetate, butyl acetate and ethyl formate), ketones (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and acetophenone) aldehydes (such

as acetaldehydes and benzaldehyde) and carboxylic acids (such as formic acid, trifluoroacetic acid and acetic acid). Where appropriate, the dipolar organic compound may act as a solvent for the reaction.

The dipolar organic compound and/or nucleophilic source can be added in any amount from 0. 1% to a large excess based on the amount of endosulfan (or endosulfan diol).

In one embodiment, the nucleophilic source is soluble in the reaction medium and able to dissociate in the reaction mixture to produce the nucleophile. In another embodiment, the nucleophilic source is loaded onto an insoluble (in the reaction medium) support, such as an ion exchange resin, which can be intimately contacted with the dipolar organic compound to generate the nucleophile. The nucleophilic source must not undergo substantial irreversible reaction with endosulfan.

The addition of an acid is optional but may facilitate an increase in reaction rate. Suitable acids for the isomerization process include strong acids with a pka, relative to water, of <3, including inorganic and organic acids, such as hydrogen chloride, hydrogen bromide, sulfuric acid, toluene sulfonic acid, methane sulfonic acid, or trifluoracetic acid. The acid must be sufficiently strong to protonate the endosulfan molecule but must not promote substantial irreversible reactions with the dipolar organic compound or the endosulfan molecule. Suitable acids may also include Lewis acids such as A1C13 and BF3.

The isomerization may be performed at a temperature in the range of-30 to 160°C. The temperature is not critical, although the rate of isomerisation is faster at higher temperatures.

The isomerization process can be carried out at any suitable concentration of endosulfan in solvent greater than 1 mg/L, up to saturation point. Preferably, the concentration of endosulfan is in the range of about lg/L to 700 g/L, preferably from about 5g/L to 500g/L, more preferably from about 40g/L to 400 g/L. The isomerization process may also be carried out on a suspension of endosulfan in solvent, although it would be recognised that

the effective concentration in solution would generally not exceed saturation. Suitable suspensions might be achieved in the range of lkg endosulfan/L solvent to 2kg endosulfan/L solvent.

In a preferred embodiment, the isomerization process is performed on 0-isomer enriched endosulfan prepared by the synthetic method according to the present invention.

It has further been discovered that a-endosulfan can be isomerised without, or minimal, formation of by-products (for example, less than 20%, preferably less than 10%, more preferably less than 5% and most preferably less than 1%) by using a suitable dipolar organic compound and/or organic soluble salt (in the optional presence of acid) under substantially anhydrous conditions. For example, mixtures containing a-endosulfan can be isomerised to a mixture of isomers enriched with the 0-a-isomer. The process affords fewer by-products than that previously described.

The solvent for the reaction process is also not critical in most cases, the main requirements for the solvent being that it should be capable of dissolving both endosulfan and the nucleophile source and allow it to dissociate to provide a significant proportion of the free nucleophile. It should not be substantially destroyed under the conditions of the process. Suitable examples of solvents may include the dipolar compounds described above, where appropriate, as well as hydrocarbon and chlorinated hydrocarbon solvents such as toluene, benzene, xylene, CH2C12, CHC13 and CCl4, or mixtures thereof.

To further enrich the proportion of (3-endosulfan in endosulfan obtained from the processes described herein, the obtained endosulfan can be further subjected to fractional crystallisation, for example, by cooling and/or concentrating a solution containing the endosulfan product, optionally adding a suitable hydrocarbon solvent. Methods therefor are known in the artll. Fractional crystallisation of p-endosulfan can further entail the addition of a hydrocarbon compound, in which p-endosulfan is essentially insoluble, to the solution of endosulfan. Suitable hydrocarbon compounds, include alkanes, (eg C5-C20) and petroleum ether.

In yet another embodiment of the invention, the isomerisation process of the invention can be carried out simultaneously (ie, "one-pot") with a fractional crystallisation process.

Thus, the p-isomer can be fractionally crystallised from a solvent mixture containing a strong acid (optional) and a dipolar organic compound and nucleophilic source under substantially anhydrous conditions. In this way, isomerisation of the a-isomer remaining in solution continues thus, under these conditions, the proportion of endosulfan converted to the p-isomer is further increased and a greater amount of p-endosulfan can be recovered than would be expected from its equilibrium concentration in the solution. This process of simultaneous isomerisation and fractional crystallisation can be effected by taking a solution of the mixed isomers in a suitable solvent or solvent mixture containing the dipolar organic compound and nucleophilic source and optional acid and effecting crystallization. If necessary, crystallization may be induced and/or the quantity of crystals increased by cooling or removing some or all of the solvent (eg, by distillation or evaporation), optionally with the addition of a solvent in which the P-endosulfan is essentially insoluble, such as a hydrocarbon solvent (for example, alkanes such as Cg-Czo alkanes).

Thus in a further embodiment of the invention, there is provided a method for preparing endosulfan enriched in the p-isomer comprising the steps of : (a) treating a mixture of a-and p-endosulfan with a nucleophile, optionally in the presence of an acid, under substantially anhydrous conditions; (b) optionally adding a hydrocarbon solvent; (c) cooling or concentrating the mixture to precipitate p-endosulfan, and (d) collecting the precipitated p-endosulfan ; wherein steps (b) and (c) can be conducted in reverse order.

The precipitated p-endosulfan is preferably collected by filtration. Optionally the collected precipitate is further washed with a hydrocarbon solvent.

In this manner, (3-endosulfan may be produced in high purity by crystallisation, typically

with a P-isomer content above 90%. p-Endosulfan may also be produced in lower purity by removal of most of the solvent and dipolar organic compound and allowing the resulting product to solidify to give a product with an enriched level of the R-isomer.

Alternatively, the isomer mixture may be stabilised by removing the dipolar organic compound or nucleophilic source or by neutralising the acid, or a combination of these, and a solution of the enriched p-endosulfan product may be prepared for direct formulation.

Endosulfan may also be produced by conventional synthesis 2, 3 with a predominance of the a-isomer and converted to endosulfan with an enhanced level of p-isomer by isomerization and fractional crystallization in the manner described above. The isomerization and crystallization may be performed simultaneously or sequentially and the p-cnriched product recovered by methods previously described.

The isomerization conditions may also be incorporated into a process for the synthesis of endosulfan from endosulfan diol. Advantageously, this provides an endosulfan product having typically 50-60% p-endosulfan compared to approximately 30% p-endosulfan of the commercially available product.

The method is particularly advantageous in that the acid (HC1 or HBr) generated from the reaction between the thionyl halide and the endosulfan diol provides both the nucleophile and acid when conducted in the presence of a suitable dipolar organic solvent i. e. , a thionyl halide compatible dipolar organic compound.

The synthesis may be carried out at any suitable temperature in the range of about-30°C to about 160°C. Preferably, the reaction is carried out at ambient temperatures or with mild heating, for example in the range of about 15°-40°C such as 20°-30°C.

Thionyl chloride, thionyl bromide or the compatible dipolar organic compound may be used as a solvent for the synthesis reaction mixture. Alternatively, the reactants may be dissolved in a suitable hydrocarbon or chlorinated hydrocarbon solvent such as toluene,

benzene, xylene, CH2C12, CHC13, CCI4 or hexachlorocyclopentadiene.

Suitable dipolar organic compounds to be used in the synthesis process must not be substantially reactive with the thionyl halide, ie must be thionyl halide compatible and include nitriles, amides, N-alkyl pyrrolidones, fatty acid amides, ureas and alkyl ureas, sulphoxides, nitro compounds, phenols and esters as mentioned above.

Thus, the invention provides a method for preparing endosulfan enriched in the p-isomer comprising the step of reacting endosulfan diol with thionyl halide in the presence of a thionyl halide compatible dipolar organic compound under substantially anhydrous conditions.

Further isomerisation can be performed as an entirely separate process or in the same reaction vessel at the end of the endosulfan synthesis, when the reaction of endosulfan diol with thionyl halide is complete, i. e. as a"one-pot"process. If the isomerisation is carried out immediately after the synthesis of endosulfan, and hydrogen chloride or hydrogen bromide is still present from the reaction, it may not be necessary to add more acid along with the dipolar organic compound and nucleophilic source.

The overall efficiency of the manufacturing process may be increased through the recycling of filtrates containing mixtures of a-and (3-isomers. For example, filtrates from the fractional crystallisation of (3-endosulfan from mixtures of isomers may be recycled into previous steps in the manufacturing process. The filtrates may be enriched with a- isomer without detriment to the recycle. Filtrates may be recycled by addition to a subsequent synthesis of endosulfan, if necessary after concentrating the material or removing dipolar organic materials that would be destroyed in the synthesis process.

Filtrates may also be recycled by hydrolysing to produce endosulfan diol, which may then be added to a subsequent synthesis of endosulfan. This is illustrated in Figure 1.

The endosulfan product enriched in the p-isomer and the substantially pure P-endosulfan obtained by the processes described herein can be formulated in the usual manner for

application to agricultural crops and may take the form of a solution, dispersion, aqueous emulsion or suspension powder or granules. The present invention therefore also provides a formulation or composition comprising endosulfan enriched in the 0-a-isomer, or substantially pure endosulfan as obtained by the processes described herein, together with one or more agriculturally acceptable additives. Suitable additives include solvents and surface active agents, such as dispersing, wetting or emulsifying agents known in the art.

Some examples of suitable methods and additives for preparing endosulfan formulations can be found in US 5,531, 995,3, 952,102, 3,996, 375,5, 653,973, 4, 804, 399,5, 753,591, 5,549, 903 and 6,294, 570.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

The invention will now be described with reference to the following examples which are provided to illustrate certain embodiments of the invention and are not intended to limit the generality hereinbefore described.

EXAMPLES Analysis of a-and p-endosulfan isomers was conducted with a Perkin Elmer AutoSystem XL gas chromatograph fitted with a flame ionisation detector and a 30M X 0.32mm DB17 (J&W Scientific) column. Typical retention times of a-and p-endosulfan were 6.2 minutes and 9.9 minutes, respectively.

Example 1 This example illustrates the synthesis of technical grade endosulfan from endosulfan diol (1,4, 5,6, 7,7-hexachloro-2, 3-bis (hydroxymethyl) -bicyclo [2: 2: 1] hept-5-ene) using the process described by Geering et al. in US Patent No. 2,983, 732 (1961).

Three grams of endosulfan diol was placed in a two-necked flask fitted with a condenser and pressure-equalising dropping funnel. The condenser exit was scrubbed. Three millilitres of toluene was added to the reaction flask and agitation commenced. One-hundred and ninety- eight milligrams of thionyl chloride was added to the suspension over five seconds and the mixture heated to reflux over 2h. The resulting solution was cooled and a sample taken for analysis by GC-FID. The ratio of a-to p-endosulfan in this solution was found to be 65: 35.

Example 2 This example illustrates the synthesis of (3-enriched endosulfan from endosulfan diol using thionyl chloride and acetonitrile.

One-hundred grams of endosulfan diol was placed in a two-necked flask fitted with a dropping funnel and a condenser. The condenser exit was scrubbed. Three hundred millilitres of acetonitrile was added to the reaction flask and agitation commenced. Forty- four grams of thionyl chloride was added to the suspension over ten seconds and the mixture stirred at room temperature for ten minutes. After this time, the flask was heated to 40°C and vacuum distillation commenced. Distillation continued until a final head pressure of-90kPa was reached and approximately three hundred millilitres of distillate were collected. The residue solidified upon cooling and, upon analysis by GC-FID, was found to contain enriched endosulfan (44% a-endosulfan and 56% p-endosulfan).

Example 3 This example illustrates that under substantially anhydrous conditions a-enriched endosulfan is isomerised to (3-enriched endosulfan and does not produce substantial amounts of endosulfan diol or endosulfan ether by-products.

3-1 Hydrogen chloride gas was passed through twenty millilitres of acetonitrile. The final concentration of hydrogen chloride in the acetonitrile solution was 0.3 mol dm. One gram of a-enriched endosulfan (ratio of 71: 29 a-to p-endosulfan) was dissolved in the acidified acetonitrile and the mixture agitated for 5 minutes at room temperature. The mixture was then filtered and allowed to stand at room temperature overnight. The solution was analysed by GC-FID and found to contain a ratio of a-to P-endosulfan of 41: 59, with no substantial amounts of endosulfan diol or endosulfan ether detected.

3-2 A comparison with a process which utilizes 5g technical grade endosulfan (7: 3, a- : (3- isomers) in 60 ml acetone, 40 ml toluene and 1 ml aqueous 32% HC1 is depicted below. Reaction % a % (3 % diol % other 3-1 41 59 not detected not detected 3-2 23 34 37 9 Example 4 This example illustrates simultaneous isomerisation and crystallisation under substantially anhydrous conditions and the utility of this process for obtaining multiple crops of ß- endosulfan from a-enriched endosulfan.

One-hundred millilitres of methyl ethyl ketone was sparged with hydrogen chloride gas until the concentration of hydrogen chloride in solution was 0.3 mol dom'3. This solution was

added to fifty grams of a-enriched endosulfan (97.2% w/w endosulfan; ratio a: p-=71 : 29).

The solution was filtered and cooled to 6°C overnight, after which the crystalline precipitate was collected by filtration to yield (3-enriched endosulfan (15. 5g ; ratio a: P=4 : 96). A further charge of 15. 5g of a-enriched endosulfan, identical to that charged initially, was made to the filtrate from the first isomerisation and crystallisation cycle. After cooling overnight at 6°C the crystalline precipitate was collected by filtration to yield p-enriched endosulfan (17.7g, ratio a: ß=2 : 98). The filtrate was analysed and found to contain a-enriched endosulfan (ratio a: ß=60 : 40). A further charge of 17. 5g of a-enriched endosulfan, identical to that charged initially, was made to the filtrate from the second isomerisation and crystallisation cycle.

After cooling over two nights at 6°C the crystalline precipitate was collected by filtration to yield p-enriched endosulfan (24. 5g, ratio a: ß=2 : 98). The filtrate was analysed and found to contain p-enriched endosulfan (ratio a: p=47 : 53). A summary of the endosulfan mass-balance after three isomerisation and crystallisation cycles is tabulated below and shows that a total of 56.9g of p-endosulfan is obtained from a total charge of 80.7g of a-enriched endosulfan (ratio a: ß=71 : 29). eMendM malajmSK 'j-Sm gMrgg 'jjRarga ! '' 'c. tSornt) soHierisaSh (g Tota a' char'e, : char er" char e F : content, isomerisatson 80. 7 57. 3 23. 4 56. 9 33. 5g *Includes p-endosulfan in final filtrate.

Example 5 This example illustrates that a-enriched endosulfan can be isomerised to (3-enriched endosulfan using a soluble organic salt under substantially anhydrous conditions.

A series of bottles were prepared containing an accurate charge of l. Og of endosulfan prepared as previously described in Example 1 with a ratio of a-to P-endosulfan of 71: 29.

As described in the table below, twenty millilitres of either toluene, methyl ethyl ketone (MEK) or acetonitrile (MeCN) were added to the bottles along with varying amounts of

tetrabutylammonium bromide (TBAB) and trifluoroacetic acid (TFA) in such a way as to generate the experiment set out in the table below. Each flask was agitated until complete dissolution had occurred, and then the contents were filtered into a glass bottle, which was sealed. The twelve bottles were allowed to stand at room temperature for 40h after which the ratio of a-to p-endosulfan was determined by GC-FID. +a. o, ; ,"y :. u"p ; y O. 1 sk ; Solven.- ;. TBAB i. =TFA m f,/o a=endosulfan v :/o-encl'osulfan y z., .. . r 1 Toluene 0 0 71 29 2 20 71 29 3"160 0 69 31 4"160 20 63 37 5 MEK 0 0 71 29 6"0 20 71 29 7 ll 160 0 71 29 8"160 20 41 59 X MeCN 0 0 71 29 10 0 20 71 29 11 160 0 67 33 12 160 20 43 57

REFERENCES 1. The e-Pesticide Manual, 12th Edc. , V2.0, Ed. C. D. S. Tomlin, 2000-2001 2. Frensch et al, DE 1, 015, 797 (1957) 3. Geering et al, US 2,983, 732 (1961) 4. Schmidt et al. J. Agric. Food Chem., 2001,49, 5372 and references cited therein.

5. WO 0239816 6. Schlichting, US 3,251, 856 (1966) 7. Schliiter et al, Z. Naturforsch, 1973,286, 741 8. Schumacher et al, Tetrahedron Lett., 1971,24, 2229 9. Schmidt et al., J. Agric. Food. Chem., 1997,45, 1023 and references cited therein.

10. WO 02085884 11. Mullin, J. W., Crystallization and Precipitation, in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH Verlarg GmbH, Weinheim, Germany, 2002