PROCESS FOR THE PREPARATION OF THIADIAZOLE DERIVATIVES

The present invention relates to a process for the preparation of thiadiazole derivatives and more specifically to a new synthetic process of compounds having general formula (I)

STATE OF THE ART

The compounds having general formula (I) bearing a thiadiazole ring connected to a fluoroalkenyl chain (X = F) by means of a sulfinyl (m = 1) or sulfonyl (m = 2) spacer have been described by the Applicant in Italian patent application 10201500054312 and claimed for use as nematocides in the agronomic field.

The synthetic strategy used for the preparation of the compounds having formula (I) provided for the oxidation of the compounds having formula (II) by the use of an oxidizing agent in an appropriate solvent according to scheme 1 :

Scheme 1

The compound having formula (II) was in turn obtained by reacting a compound having formula (III) with a compound having formula (IV) wherein Z represented a leaving group, such as a Cl, Br, I atom, or a p-toluenesulfonate or trifluoromethanesulfonate group, in the presence of an organic or inorganic base, according to scheme 2:

Scheme 2

(III) (IV) (II)

Alternatively, the compounds having general formula (I) can be synthesized by the synthetic route described in scheme 3 which provides the following succession of five steps, according to what has been extensively described, for the various synthetic steps in literature, for example in "South African Journal Chem. ", (2013), pages 130-135, in" Helvetiva Chimica Acta "(1974), vol.57, pages 23-32, in WO 2015/42212 (2015) and in US7238689 (2007).

Scheme 3:

(VI) (V)

The use of this synthetic procedure, however, involves the formation of the intermediate methyl hydrazine-carbodithioate (X) with the simultaneous presence in the reaction environment of the impurity dimethylthiothiadiazole having formula (IX) which, in addition to lowering the yield, requires a purification step of the raw product obtained, aggravating the whole synthetic process which already consists of numerous steps and thus bringing the whole synthesis sequence to an overall medium/low yield.

Furthermore, the double oxidation necessary for preparing the intermediate having formula (V) and the compounds having formula (I), involves a conspicuous use of oxidants which, during the whole reaction, must be handled with caution due to their reactivity and danger.

The synthetic strategy described in scheme 2, on the other hand, for those meanings of R for which the corresponding thiadiazoles are not commercial products, implies the preparation of the same thiadiazoles according to scheme 4: Scheme 4

(XV) (XI) (XIV)

(XIV) (III) (XIII)

The use, as starting reagent, of the hydrazide having general formula (XV) avoids the formation, as impurity, of dimethylthiothiadiazole (IX) obtained, as specified above, following scheme 3, but involves the generation of the disulfide having formula (XIII) during the cyclization of the intermediate (XIV) in the acid reaction environment, thus lowering the yields of the desired product and requiring a purification of the same. Furthermore, the mercaptothiadiazole having formula (III) is partially soluble in water and this makes the recovery of the product from the reaction environment difficult and never quantitative.

The above-mentioned methodologies therefore provide the compounds having general formula (I) with low yields and in the presence of various impurities, thus making it difficult to use these processes at an industrial level.

The need for identifying new methods involving the use of new intermediates for the preparation of the compounds having general formula (I) is therefore particularly felt, guaranteeing improved processes for the synthesis of thiadiazole rings connected by means of a spacer to a fluoroalkenyl chain, with high yields, with a reduction of the impurities and therefore the consequent necessary purification steps, which make use of non-toxic reagents and mild reaction conditions.

DESCRIPTION

The Applicant has now found that it is possible to obtain the compounds having general formula (I) by using new synthetic routes which overcome the drawbacks and have numerous advantages with respect to the known art described above. More particularly, at an industrial level, the objective of the present invention is a preparation process having a reduced number of synthesis steps, with the use of less dangerous reagents and with much higher overall yields with a greater atomic efficiency.

Furthermore, said new synthetic processes are particularly advantageous due to the possibility of carrying out the various steps in sequence, without isolating the intermediates and without the need for their purification.

A first object of the present invention therefore relates to a synthetic process of compounds having general formula (I)

wherein

X represents a fluorine or hydrogen atom;

n represents a number ranging from 1 to 6;

m is equal to 1 or 2;

R represents a Ci-C ₆ alkyl group, a Ci-C ₆ haloalkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₄ -C ₇ cycloalkylalkyl group, or an aryl optionally substituted,

by means of an oxidation reaction of a thioether having general formula

(P)

said thioether having general formula (II) being obtained by means of a cyclization reaction in an acidic or basic environment, starting from compounds having general formula (XVIa)

wherein:

X and n have the meanings previously indicated,

Q' represents an acyl group having formula RC(O)- wherein R has the meanings previously indicated.

The compounds having general formula (XVIa)

can be obtained starting from compounds having general formula (XVIb)

by means of an acylation reaction with an acyl chloride RC(0)Cl having general formula (VII)

wherein R has the meanings previously indicated, wherein the acylation reaction can be carried out upstream of or simultaneously with the cyclization reaction. Schematically, therefore, the compounds having general formula (I) can be obtained by cyclization of the intermediate (XVIa) in an acidic or basic environment to give the corresponding thioether having formula (II) and subsequent oxidation thereof, according to reaction scheme 5:

Scheme 5

(P) (I)

wherein:

X, n, and m have the meanings previously indicated, whereas, again schematically, the compounds having general formula (I) can be obtained by acylation reaction of the intermediate (XVIb) with an acyl chloride RC (O) Cl having general formula (VII), wherein R has the meanings indicated above, and simultaneous cyclization in an acidic or basic environment to give the corresponding thioether having formula (II), and subsequent oxidation of the compounds having formula (II) thus obtained, to give the compounds having general formula (I) according to reaction scheme 6:

Scheme 6

(P) (I)

Examples of Ci-C ₆ alkyl, linear or branched, are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methylbutyl, n- hexyl, 3, 3-dimethylbutyl.

Examples of Ci-C ₆ haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloro methyl, dichloro methyl, 2,2,2-trifluoroethyl, l,l,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoropropyl, 4,4,4-trichloro-butyl, 4,4-difluoropentyl, 5,5- difluorohexyl.

Examples of C3-C6 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Examples of C ₃ -Cs halocycloalkyl are 2,2-dichloro-cyclopropyl, 2,2- difluorocyclopropyl, 2,2,3,3-tetrafluorocyclobutyl, 3,3-difluorocyclopentyl, 2- fluorocyclohexyl.

Examples of C ₄ -C ₇ cycloalkylalkyl are methylcyclopropyl, methylcyclopentyl, ethylcyclopropyl, methylcyclo hexyl.

Optionally substituted aryl refers to an aryl group which can have one or more substituents, the same as or different from each other, preferably selected from the following groups: halogen atoms, Ci-C ₆ alkyls, Ci-C ₆ haloalkyls, Ci-C ₆ alkoxyls, Ci-C ₆ haloalkoxyls, C ₃ -C ₆ cycloalkoxyls, C ₄ -C ₇ cycloalkylalkoxyls, phenoxyls, Ci-C ₆ alkylthio, Ci-C ₆ halo alky lthio, Ci-C ₆ alkylsulfinyls, Ci-C ₆ alkylsulfonyls, Ci-C ₆ alkylamino, C ₂ -C ₁₂ dialkylamino, cyano, C ₂ -C ₇ alkoxycarbonyls, benzyloxycarbonyls, phenoxycarbonyls.

Aryl group refers to a phenyl or naphthyl group.

A further object of the present invention relates to the new compounds having formula (XVI):

wherein:

X represents a fluorine or hydrogen atom;

n represents a number ranging from 1 to 6;

Q represents a hydrogen atom or an acyl group having formula RC(O) wherein R represents a Ci-C ₆ alkyl group, a Ci-C ₆ haloalkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₄ -C ₇ cycloalkylalkyl group, or an aryl, optionally substituted; with the proviso that n is different from 2 when Q represents a hydrogen atom. Examples of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl substituents or optionally substituted aryl are those previously indicated. Among the compounds having general formula (I) that can be prepared starting from the compounds having general formula (XVI) of the present invention, those wherein:

X represents a fluorine atom;

n is 2;

m is 2;

R represents a Ci-C ₆ alkyl group

are preferred.

Particularly preferred are compounds having formula (I) wherein:

X represents a fluorine atom;

n is 2;

m is 2;

R represents methyl or isopropyl.

Consequently, the compounds having general formula (I) can be easily obtained in only two steps by cyclization of the intermediate (XVI) in an acidic or basic environment to give the corresponding thioether having formula (II).

The reaction can be carried out in the presence or absence of a solvent such as toluene, chloroform, dichloroethane, dioxane or in water with the addition of an acid such as sulfuric acid, phosphoric acid, polyphosphoric acid, hydrochloric acid, p-toluenesulfonic acid at a temperature ranging from -5°C to 90°C depending on the acid and solvent used. Alternatively the reaction can be carried out in a basic environment in the presence or absence of a solvent such as toluene, chloroform, dichloroethane, dioxane or in water with the addition of a base, for example inorganic, such as sodium or potassium bicarbonate or sodium or potassium carbonate as described in "Chin. J. Chem. "(2011), vol.29, pages 959-967.

The product obtained is subsequently oxidized, without further purifications, to give the compounds having formula (I) in high yields.

The conditions for carrying out this reaction, as described for example in WO 02/062770, provide for the use of an oxidizing agent in an appropriate solvent; among the oxidizing agents organic peroxides, such as 4-chloro-perbenzoic acid, peracetic acid or inorganic peroxides such as, for example, hydrogen peroxide, potassium permanganate, sodium periodate, potassium peroxymonosulfates, can be used.

The solvents used are preferably halogenated hydrocarbons such as dichloromethane or dichloroethane or chloroform, ethers such as dioxane or tetrahydrofuran, amides such as N, N-dimethylformamide or N-methyl- pyrrolidone, alcohols such as methanol, ethanol, propanol, isopropanol or ketones such as acetone or 2- butanone, acetic acid, water and mixtures thereof and the reaction temperature can range from 0 to 90 ⁰ C, for a time ranging from 1 to 72 hours depending on the oxidizing agent used.

The compounds having general formula (I) can be obtained starting from the intermediate (XVIb) as indicated above, providing that the cyclization reaction is carried out simultaneously or after the acylation reaction: in the first case (simultaneous cyclization), therefore, the compounds having general formula (I) are always synthesized in only two steps, the first comprising the acylation of the compound having formula (XVIb) with the compounds having formula (VII) and the simultaneous cyclization to give the thioether having formula (II), the second comprising the oxidation of the latter to give the compounds having formula (I). The acylation reaction can be carried out in a chlorinated solvent such as chloroform or methylene chloride or dichloroethane or in toluene or acetonitrile, at a temperature ranging from room temperature to the reflux temperature of the solvent used.

Alternatively, when the cyclization reaction is carried out following the acylation reaction, the acylation reaction can take place in a mixture of water and a water- miscible solvent, such as dioxane or tetrahydrofuran in the presence of a base such as sodium acetate and at a temperature ranging from -20°C to room temperature, as described in "Chin. J. Chem. "(2011), vol.29, pages 959-967. The product obtained having general formula (XVIa) is then cyclized to give the compound having formula (II) using the procedures indicated above.

The compounds having formula (II), prepared according to one of the methods indicated, can be directly oxidized to give the compounds having formula (I) in high yields and without further purifications, under the conditions indicated above.

The compounds having general formula (XVIa), when they are not prepared by acylation of a compound having formula (XVIb) with a compound having formula (VII) according to the above, can be easily obtained by reaction of the hydrazide having formula (XV) and carbon sulfide with the compound having general formula (IV).

The intermediate (XVIa) thus obtained can be cyclized to give the thioether having general formula (II) which is oxidized to give compound (I) with a high yield and a purity which does not require to purify the final product prepared according to reaction scheme 7 :

Scheme 7

(II) (I)

wherein Z represents a leaving group such as a halogen atom selected from Cl and Br or a -tolucncsu donate or trifluoromethanesulfonate group.

The reaction can be carried out in an appropriate solvent such as alcohols, for example methanol, ethanol, propanol, isopropanol or a mixture of alcohols and water, at a temperature ranging from 0 ⁰ C to room temperature.

The compounds having formula (IV) with Z representing a halogen atom are commercial products; the compounds (IV) for Z that represents a p- toluenesulfonate or trifluoromethanesulfonate group, can be obtained from the corresponding alcohols (XVII) as described in Theodora W. Greene "Protective Groups in Organic Synthesis" Third Edition pages 198-199 and indicated in scheme 8:

Scheme 8

(XVII) (IV)

The hydrazides having formula (XV), when they are not commercial, can be prepared starting from the corresponding acids or esters with hydrazine hydrate according to methods well known in literature and described for example in "Journal Heterocyclic Chem" (2010), vol.47, pages 838-845 or in "Medicinal Chemistry", (2013), vol.9, pages 968-973.

The compounds having general formula (XVIb), for n other than 2, can be easily obtained by reaction of the hydrazine and carbon disulfide with the compound having general formula (IV) according to reaction scheme 9:

Scheme 9

(IV) (XVIb)

wherein Z has the same meanings described above.

The reaction can be carried out in an appropriate solvent such as alcohols, for example methanol, ethanol, propanol, isopropanol or a mixture of alcohols and water, at a temperature ranging from 0°C to room temperature.

Some examples are now provided which should be considered as being descriptive and non-limiting of the present invention.

EXAMPLE 1

Preparation of 2-(3,4,4-trifluoro-3-butenylsulfonyl)-5-isopropyl-l,3,4- thiadiazole [Compound having general formula (I) R = i-propyl, preparation according to scheme 6\.

a) Preparation of 3.4.4-trifluoro-3-butenyl hvdrazine-carbodithioate [Compound having general formula (XVIb)l.

8.7 ml (144 mmoles) of carbon disulfide diluted in 40 ml of isopropanol were slowly added dropwise to a solution of 10.32 g of hydrazine monohydrate (206 mmoles) and 11.56 g of potassium hydroxide (206 mmoles) in a mixture of water (80 ml) and isopropanol (70 ml), maintaining the temperature at around -5°C. At the end of the addition, lasting 3 hours, a whitish suspension was obtained to which 16.7 ml (144 mmoles) of 4-bromo-l,l,2-trifluorobutene were added dropwise on an ice bath at about 0°C. After an hour the reaction mixture was left to return to room temperature and left under stirring at this temperature for 24 hours.

After control with LC-MS, the alcohol solvent was removed by rotary evaporation at reduced pressure and the aqueous phase extracted with dichloro methane 3 times. The combined organic phases were washed with a saturated sodium chloride solution, anhydrified on sodium sulfate, filtered and evaporated to give 28.5 g of product which was used as such for the subsequent reaction.

Yield: 96%

LC-MS: M ⁺ = 217 b) Preparation of 2-(3.4.4-trifluoro-3-butenylthio)-5-isopropyl-L3.4-thiadiazo le IThiocthcr having general formula 1

11.87 ml (113.3 mmoles) of isobutyryl chloride and 1.66 ml (10.3 mmoles) of POCI ₃ were added dropwise at room temperature to a solution of 22.25 g (103 mmoles) of the product obtained in step a) in 600 ml of chloroform. The reaction mixture was then brought to the reflux temperature of the solvent and left under stirring for 8 hours at this temperature.

After LC-MS control, the reaction mixture was carefully poured into water and ice and recovered with dichloro methane. After the phase separation, the organic phase was washed with a 5% NaOH solution, then twice with water until neutrality, finally with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 26 g of raw product.

The product thus obtained was used for the subsequent reaction.

Yield: 94.1%

LC-MS: M ⁺ = 269

Alternatively

b’) Preparation of 2-(3.4.4-trifluoro-3-butenylthio)-5-isopropyl-l.3.4-thiadiaz ole IThiocthcr having general formula (11)1

26.98 ml (257.5 mmoles) of isobutyryl chloride were added dropwise at room temperature to a solution of 22.25 g (103 mmoles) of the product obtained in step a) in 600 ml of chloroform. The reaction mixture was then brought to the reflux temperature of the solvent and left under stirring for 8 hours at this temperature. After LC-MS control, the reaction mixture was carefully poured into water and ice and recovered with dichloro methane. After the phase separation, the organic phase was washed with a 5% NaOH solution, then twice with water until neutrality, finally with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 26.22 g of raw product.

The product was thus used for the subsequent reaction without further purification.

Yield: 95%

LC-MS: M ⁺ = 269

c) Preparation of 2-(3.4.4-trifluoro-3-butenylsulfonyl)-5-isopropyl- 1.3.4- thiadiazole I Compound having general formula (1) R = isopropyll

0.615 g (1.87 mmoles, 2%) of sodium tungstate Na ₂ W0 ₄ *2H ₂ 0 were added to a solution of 25 g (93.3 mmoles) of the compound obtained in step b) in 120 ml of acetonitrile, followed by 5.5 ml of water. The reaction mixture was cooled to 20°C and 27.2 ml (280 mmoles) of a 35% aqueous solution of H ₂ 0 ₂ were slowly added dropwise, maintaining the internal temperature below 25 °C. It was then slowly heated to 50°C and kept at this temperature for about 12 hours.

After control in LC-MS, 8.8 g (46.6 mmoles) of sodium metabisulfite were carefully added, in portions, to the mixture, brought back to room temperature. Stirring was maintained for about 30 minutes until the complete absence of oxidizing conditions had been confirmed, controlled by a starch indicator and KI. After the removal of most of the organic solvent by rotary evaporation under reduced pressure, the aqueous phase was extracted with dichloro methane 3 times. The combined organic phases were washed with a 5% NaOH solution, then twice with water until neutrality, finally with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 30 g of raw product.

The product thus obtained was purified by rapid passage over silica gel, eluting with toluene. 26.5 g of the desired product were obtained.

Yield: 94.6%

Overall yield over 3 steps: 85.4% (with reaction b)), 86.3% (with reaction b’) LC-MS: M ⁺ = 301

EXAMPLE 2

Preparation of 2-(3,4,4-trifluoro-3-butenylsulfonyl)-5-isopropyl-l,3,4- thiadiazole [Compound having general formula (I) R = isopropyl preparation according to scheme 5].

a) Preparation of 3.4.4-trifluoro-3-butenyl 2-isobutyryldithiocarbazate I Compound having general formula (XVIa)l.

6.5 ml (107.7 mmoles) of carbon disulfide were slowly added dropwise to a solution of 10.00 g of isobutyryl hydrazide (97.9 mmoles) and 10.98 g of potassium hydroxide (195.8 mmoles) in methanol (60 ml), maintaining the temperature at a value of 0 to 5°C. After an hour at this temperature, a yellowish suspension was obtained to which 12.5 ml (107.7 mmoles) of 4-bromo- 1,1,2- trifluorobutene were added dropwise on an ice bath at about 0°C. After an hour, the reaction mixture was allowed to return to room temperature, as the turbidity gradually increases due to the formation of KBr and is produced and left under stirring at this temperature for 2 hours. After LC-MS control, the alcohol solvent was removed by rotary evaporation at reduced pressure and the aqueous phase was extracted with dichloro methane 3 times. The combined organic phases were washed with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 26 g of the desired product, used without further purification in the next step.

Yield: 92.8%

LC-MS: M = 285

b) Preparation of 2-(3.4.4-trifluoro-3-butenylthio)-5-isopropyl-L3.4-thiadiazo le I Compound having general formula (

22.6 g (79.0 mmoles) of the product obtained in step a) were charged into a 500 ml flask and 15 ml (282 mmoles) of H ₂ SO ₄ were added dropwise at 0°C. The reaction mixture was stirred slowly so as to make it homogeneous, maintaining the temperature at a value of 0 to 5°C and left under stirring for 8 hours at this temperature.

After LC-MS control, the reaction mixture was carefully poured into water and ice and recovered with dichloro methane. After the phase separation, the organic phase was washed with a 5% NaOH solution, then twice with water until neutrality, finally with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 19.8 g of raw product.

The product obtained was subjected to the oxidation reaction of the subsequent step.

Yield: 92.5%

LC-MS: M ⁺ = 269 c) Preparation of 2-(3.4.4-trifluoro-3-butenylsulfonyr)-5-isopropyl- 1.3.4- thiadiazole I Compound having general formula (I) R = isopropyl·!.

Starting from 21.5 g (80.2 mmoles) of the compound having formula (II) obtained in step b) and using the procedure described in reaction c) of Example 1, 22.9 g of the desired product were obtained.

Yield: 95%

Overall yield over 3 steps: 81.5%

LC-MS: M ⁺ = 301

EXAMPLE 3 (comparative)

Preparation of 2-(3,4,4-trifluoro-3-butenylsulfonyl)-5-isopropyl-l,3,4- thiadiazole [Compound having general formula (I) R = isopropyl, preparation according to scheme 3].

a) Preparation of methyl hvdrazine-carbodithioate I Compound having general formula (X)1.

36.3 ml (600 mmoles) of carbon disulfide were slowly added dropwise to a solution of 33.6 g (600 mmoles) of hydrazine monohydrate and 39.6 g (600 mmoles) of 85% potassium hydroxide in 300 ml of methanol, maintaining the temperature at around 0°C. After 1 hour, 37.4 ml (600 mmoles) of methyl iodide were added dropwise onto an ice bath at about 0°C. After an hour, the reaction mixture was left to return to room temperature and left under stirring at this temperature for 24 hours.

After LC-MS control, the alcohol solvent was removed by rotary evaporation at reduced pressure and the aqueous phase was extracted with ethyl ether 3 times. The combined organic phases were washed with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 20 g of product, containing, as by-product, 2,5-dimethylthio-l,3,4-thiadiazole having formula (IX).

The product thus obtained was purified by re-crystallization from toluene to give 16.1 g of the desired product.

Yield: 22%

LC-MS: M ⁺ = 123

b) Preparation of 5-isopropyl-2-methylthio-l.3.4-thiadiazole I Compound having general formula (VI)1

16.1 g (131 mmoles) of the product obtained in step a) and 11.6 g (131 mmoles) of isobutyric acid were mixed in a flask and the reaction mixture was brought to a temperature of 0°C. 27.7 ml (303 mmoles) of POCl ₃ were then added dropwise. The reaction mixture was then brought to a temperature of 80°C and left under stirring for 3 hours at this temperature.

After LC-MS control, the reaction mixture was carefully poured into water and ice and recovered with ethyl acetate. The phases were separated and the organic phase was washed with a 5% NaOH solution, then twice with water to neutrality, finally with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 19.5 g of raw product, such as yellow oil, used without further purifications in the next step.

Yield: 85.5%

LC-MS: M ⁺ = 175 c) Preparation of 5-isopropyl-2-methanesulfbnyl-l.3.4-thiadiazole I Compound having general formula (V)1.

75.5 g (336 mmoles) of meta-chloroperbenzoic acid at 77% were added, on an ice bath, in small portions, to a solution of 19.5 g (112 mmoles) of the compound obtained in step b), in 500 ml of chloroform and the whole mixture was left under cold stirring for about 1 hour. The temperature was then left to rise to environmental values and the stirring was continued for 4 hours. The reaction mixture was filtered to remove the excess oxidant and subsequently washed with a 2% aqueous solution of Na ₂ S ₂ 0 ₅ , then with a 5% NaOH solution and finally with water to neutrality. After anhydrification on sodium sulfate, filtration and evaporation, 20.3 g of a whitish solid were obtained, used without further purification in the following step.

Yield: 88%

LC-MS: M ⁺ = 207

d) Preparation of 2-(3.4.4-trifluoro-3-butenylthio)-5-isopropyl-l.3.4-thiadiaz ole I Compound having general formula (11)1

6.8 g (84.75 mmoles) of NaSH (70%) were added at room temperature to a solution under nitrogen of 7 g (33.9 mmoles) of 5-isopropyl-2-methanesulfonyl- l,3,4-thiadiazole in 110 ml of dimethylformamide; the mixture was left under magnetic stirring at room temperature for two hours. After control in GC-MS, 4.7g (33.9 mmoles) of potassium carbonate, 4.6 g (33.9 mmoles) of sodium hydro xymethanesulfinate ( Rongalit ) and 6.4 g (33.9 mmoles) of 4-bromo- 1,1,2- trifluorobut-l-ene were added in order. The mixture was left under magnetic stirring at room temperature overnight.

After control in GC-MS and LC-MS, the mixture was poured into water; the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.1 g of the desired product were obtained.

Yield: 78.1%

LC-MS [M+H] = 269.

e) Preparation of 2-(3.4.4-trifluoro-3-butenylsulfonyl')-5-isopropyl- 1.3.4- thiadiazole I Compound Nr. 11.

22.40 g (79.5 mmoles ) of 4-chloroperbenzoic acid at 77% were added to 7.1 g (26.5 mmoles) of 2-(3,4,4-trifluoro-3-butenylthio)-5-isopropyl-l,3,4-thiadiaz ole, dissolved in 30 ml of chloroform, maintaining a temperature of about 4-5°C with an ice bath. The mixture was left under magnetic stirring at room temperature overnight.

After LC-MS control, the mixture was diluted with water and the phases were then separated; the aqueous phase was re-extracted twice with dichloromethane. The combined organic phases were washed with an aqueous solution of NaHSCL at 5%, a saturated solution of NaHC0 ₃ , water and a saturated solution of NaCl. After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 6.5 g of raw product were obtained, which was purified by chromatography on silica gel eluting with a mixture of heptane: ethyl acetate 7: 3. 5.56 g of the desired product are obtained as a yellowish/brown oil. Yield: 70%

Overall yield over 5 steps: 9% LC-MS [M+H] = 301