PROCESS OF PREPARING 2-(PHENYLIMINO)-3-ALKYL-1,3-THIAZOLIDIN-4-ONES

Abstract

The present invention relates to a method for preparing 2-(phenylimino)-3-alkyl-1,3-thiazolidin-4-ones of the general formula (I)

##STR00001##

in which Y.sup.1, Y.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined in the description.

Claims

1. A method for preparing 2-(phenylimino)-3-alkyl-1,3-thiazolidin-4-one of formula (I) ##STR00032## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, and R.sup.3 is optionally substituted (C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.12)alkyl or (C.sub.1-C.sub.12)haloalkyl, in which the substituents are selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, cyano, nitro, hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl and (C.sub.1-C.sub.6)haloalkoxy, Comprising reacting a 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII) ##STR00033## in which Y.sup.1, Y.sup.2, R.sup.1 and R.sup.2 are as defined above, with an alkylating agent of formula (IX)
R.sup.3—Z  (IX) in which R.sup.3 is as stated above and Z is OSO.sub.2F in the presence of a base and a solvent.

2. The method according to claim 1, wherein the compound of formula (VIII) is obtained from monoarylthioureas of formula (XII) ##STR00034## in which, Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, by reaction with a compound of formula (III) ##STR00035## in which X is bromine, chlorine, OSO.sub.2Me, OSO.sub.2Ph, OSO.sub.2(4-Me-Ph) or OSO.sub.2CF.sub.3 and W is OH or an O(C.sub.1-C.sub.6 alkyl) radical.

3. The method according to claim 2, wherein the monoarylthiourea of formula (XII) is obtained from an aniline of the formula (IV) ##STR00036## in which, Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, by reaction with an alkoxycarbonyl isothiocyanate of formula (XIII) ##STR00037## in which R.sup.4 is methyl, ethyl or isopropyl, to give an alkyl (phenylcarbamothioyl)carbamate of formula (XIV) ##STR00038## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, and R.sup.4 is as defined above, which is then saponified and decarboxylated under acidic or alkaline conditions.

4. The method according to claim 1, wherein the compound of formula (VIII) is obtained from a 2-halo-N-(phenyl)acetamide of formula (XV) ##STR00039## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro and Hal is chlorine or bromine, by reaction with an alkali metal or ammonium rhodanide of formula (XVI)
MSCN  (XVI), in which M is Li, Na, K or NH.sub.4.

5. The method according to claim 4, wherein the 2-halo-N-(phenyl)acetamide of the formula (XV) is obtained from an aniline of formula (IV) ##STR00040## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, by reaction with a haloacetyl halide of formula (XVII) ##STR00041## in which H is chlorine or bromine and Hal′ is chlorine or bromine.

6. The method according to claim 1, wherein Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently fluorine, chlorine, (C.sub.1-C.sub.3)alkyl or hydrogen, R.sup.3 is (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)haloalkyl, and Z is OSO.sub.2F.

7. The method according to claim 1, wherein Y.sup.1 and Y.sup.2 are each independently fluorine or hydrogen, R.sup.1 and R.sup.2 are each independently fluorine, chlorine, hydrogen or methyl, R.sup.3 is (C.sub.1-C.sub.6)haloalkyl, and Z is OSO.sub.2F.

8. The method according to claim 1, wherein Y.sup.1 and Y.sup.2 are fluorine, R.sup.1 and R.sup.2 are each independently fluorine, hydrogen or methyl, R.sup.3 is (C.sub.1-C.sub.6)fluoroalkyl, and Z is OSO.sub.2F.

9. The method according to claim 1, wherein Y.sup.1 and Y.sup.2 are fluorine, R.sup.1 is methyl, R.sup.2 is fluorine, R.sup.3 is CH.sub.2CF.sub.3, and Z is OSO.sub.2F.

10. The method according to claim 2, wherein X is bromine or chlorine and W is a radical O(C.sub.1-C.sub.6-alkyl), and optionally X is bromine or chlorine and W is a radical OCH.sub.3 or OC.sub.2H.sub.5, and optionally X is bromine or chlorine and W is a radical OCH.sub.3.

11. The method according to claim 3, wherein R.sup.4 is methyl or ethyl.

12. The method according to claim 4, wherein Hal is chlorine and M is Li, Na, Ka or NH.sub.4.

13. The method according to claim 5, wherein Hal′ is chlorine.

14. The method according to claim 1, wherein the compound of formula (I) is in the form of the Z-isomer or a mixture of the E- and Z-isomers in which the proportion of the Z-isomer is greater than 50%, based on the total amount of E- and Z-isomers in the mixture.

15. The method according to claim 1, wherein the reaction of the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII) to give the compound of formula (I) is carried out in the presence of a solvent selected from dichloromethane, acetonitrile, propionitrile, butyronitrile, ethyl acetate, butyl acetate, toluene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, sulfolane and mixtures thereof.

16. The method according to claim 1, wherein the reaction of the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII) to give the compound of formula (I) is carried out in the presence of a base which is selected from trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, pyridine, 2-methylpyridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 2-methyl-5-ethylpyridine, quinoline, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium acetate, sodium acetate, lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate and magnesium carbonate.

17. The method according to claim 1, wherein said method is carried out at a temperature between −20° C. and 150° C.

18. The method according to claim 1, wherein the alkylating agent R.sup.3—Z of formula (IX) is used at a molar ratio from 0.9:1 to 2:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII).

19. The method according to claim 1, wherein the base is used at a molar ratio from 0.9:1 to 4:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII).

20. The method according to claim 1, wherein the compound (IX) is prepared in situ by reacting a compound of formula (XI)
R.sup.3—OH   (XI) in which R.sup.3 is (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)haloalkyl, with SO.sub.2F.sub.2 or SO.sub.2ClF.

21. The method according to claim 20, wherein the compound of formula (XI) is reacted with SO.sub.2F.sub.2.

22. The method according to claim 20, wherein the alcohol R.sup.3—OH is used at a molar ratio from 1:1 to 4:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII).

23. The method according to claim 20, wherein the reagent SO.sub.2F.sub.2 or SO.sub.2ClF is used at a molar ratio from 1:1 to 4:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of the formula (VIII).

24. The method according to claim 20, wherein the base is used at a molar ratio from 1:1 to 4:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII).

25. A compound of formula (VIII) ##STR00042## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro.

26. A compound of formula (XII) ##STR00043## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro.

27. A compound of formula (XIV) ##STR00044## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro and R.sup.4 is methyl, ethyl or isopropyl.

28. The compound according to claim 27, in which R.sup.4 is methyl or ethyl.

29. A compound of formula (XV) ##STR00045## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro; and Hal is chlorine or bromine.

30. The compound according to claim 29, in which Hal is chlorine.

31. A compound of formula (VIII′) ##STR00046## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro.

32. A compound of formula (X) ##STR00047## in which Y.sup.1 and Y.sup.2 are each independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1-C.sub.12)alkyl, (C.sub.1-C.sub.12)haloalkyl, cyano, halogen or nitro, R.sup.3 is optionally substituted (C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.12)alkyl or (C.sub.1-C.sub.12)haloalkyl, in which the substituents are selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, cyano, nitro, hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl and (C.sub.1-C.sub.6)haloalkoxy.

Description

PREPARATION EXAMPLES

Example 1: Synthesis of 2-chloro-N-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}acetamide

[0170] ##STR00021##

[0171] To a solution of 11.96 g [50 mmol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline and 10.12 g [100 mmol] of triethylamine in 100 ml of methylene chloride were added dropwise 6.78 g [60 mmol] of chloroacetyl chloride at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. and then overnight at 20° C. The reaction mixture was stirred with 150 ml of water. The organic phase was separated off, the aqueous phase extracted with 50 ml of methylene chloride, the combined organic phases washed twice with 50 ml of 15% hydrochloric acid and then with 50 ml of water, dried over sodium sulfate and concentrated under reduced pressure. This gave 15 g of brownish solid which, according to GC (gas chromatography), had a purity of 96.5% (a/a), which resulted in a yield of 92.9% of theory.

[0172] Melting point: 128° C.

[0173] GC/MS: m/e=315 (M.sup.+, 1 Cl, 33%), 239 (M*-76, 43%), 156 (100%).

[0174] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.44 (s, 3H), 3.87 (q, 2H), 4.4 (s, 2H), 7.32 (d, 1H), 8.12 (d, 1H), 10.17 (s, 1H) ppm.

.sup.19F-NMR (565 MHz, d.sub.6-DMSO): δ=−64.3 (t, 3F), −124.3 (dd, 1F) ppm.

Example 2: Synthesis of methyl ({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanylphenyl}carbamothioyl)carbamate

[0175] ##STR00022##

[0176] Step 1 (preparation of methoxycarbonyl isothiocyanate): To 56.75 g [0.7 mol] of sodium thiocyanate in 300 ml of toluene was added 0.4 g of pyridine and 0.9 g of water at 30° C. Subsequently, 56.7 g [0.6 mol] of methyl chloroformate were added over 20 minutes. The mixture was stirred at 30° C. for 2 hours, cooled to 20° C. and the sodium chloride filtered off. The filtrate was used in step 2.

[0177] Step 2 (preparation of the title compound): The filtrate from step 1 was initially charged and a solution of 119.6 g [0.5 mol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline in 100 ml of toluene was added at 30° C. After completion of the addition, the mixture was heated to 80° C. and stirred for 90 minutes at this temperature. The reaction mixture was then cooled to 0° C., the precipitated solid filtered off, washed with 250 ml of pentane and dried. In this manner, 165.5 g of white solid was obtained which, according to quantitative .sup.1H-NMR, had a content of 98.1% (w/w). This therefore corresponded to a yield of 91.1% of theory.

[0178] Melting point: 153-154° C.

[0179] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.40 (s, 3H), 3.76 (s, 2H), 3.86 (q, 2H), 7.28 (d, 1H), 8.05 (d, 1H), 11.36 (s, 1H), 11.55 (s, 1H) ppm. .sup.19F-NMR (565 MHz, d.sub.6-DMSO): δ=−64.4 (t, 3F), −123.3 (dd, 1F) ppm.

Example 3: Synthesis of ethyl ({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}carbamothioyl)carbamate

[0180] ##STR00023##

[0181] Step 1 (preparation of ethoxycarbonyl isothiocyanate): To 5.35 g [0.066 mol] of sodium thiocyanate in 50 ml of acetone are added 6.51 g [0.06 mol] of ethyl chloroformate over 5 minutes. The mixture was stirred for 15 minutes under reflux, cooled to 20° C. and the sodium chloride filtered off. The filtrate was used in step 2.

[0182] Step 2 (preparation of the title compound): The filtrate from step 1 was initially charged and, at 20° C. initially without cooling, a solution of 11.96 g [0.05 mol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline in 20 ml of acetone was added. After completion of the addition, the mixture was heated for 1 hour under reflux. The reaction mixture was then cooled to 20° C., added to 370 ml of water, the precipitated solid was filtered off and dried. In this manner, 19.25 g of white solid was obtained which, according to HPLC analysis, had a purity of 92.6% (a/a). This therefore corresponded to a yield of 96% of theory.

[0183] Melting point: 126° C.

[0184] LC/MS: m/e=371 (MH.sup.+).

[0185] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=1.26 (t, 3H), 2.4 (s, 3H), 3.86 (q, 2H), 4.22 (q, 2H), 7.28 (d, 1H), 8.05 (d, 1H), 11.4 (s, 1H), 11.5 (s, 1H) ppm.

Example 4: Synthesis of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}thiourea

[0186] ##STR00024##

[0187] To a mixture of 893 ml of 1 N aqueous sodium hydroxide solution and 530 ml of ethanol charged in a 2 litre reactor were metered in 169.6 g [0.458 mol] of ethyl ({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}carbamothioyl)carbamate over ca. 10 minutes. The mixture was heated over 30 minutes to 50° C. and stirred at this temperature for 17 hours. The reaction mixture was cooled and, at about 40° C., emptied out of the reactor. At 20° C., the pH was adjusted to 6-8 with semi-concentrated hydrochloric acid. The precipitated solids were filtered off under suction, washed with water and dried. This gave 130.38 g of the title compound which, according to quantitative .sup.19F-NMR, had a content of 94.7% (w/w). This therefore corresponded to a yield of 90.4% of theory.

[0188] Melting point: 120-122° C.

[0189] LC/MS: m/e=299 (MH.sup.+).

[0190] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.37 (s, 3H), 3.85 (q, 2H), 4.22 (q, 2H), 7.22 (d, 1H), 7.86 (d, 1H), 9.38 (s, 1H) ppm.

[0191] .sup.19F-NMR (565 MHz, d.sub.6-DMSO): δ=−64.8 (t, 3 F), −123.5 (dd, 1F) ppm.

Example 5: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one

[0192] ##STR00025##

[0193] In 75 ml of acetonitrile were initially charged 14.92 g [50 mmol] of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}thiourea and 5.33 g [65 mmol] of sodium acetate. At 20 to 25° C., 9.18 g [55 mmol] of ethyl bromoacetate were added dropwise. The reaction mixture was stirred at 20° C. for 20 hours. The acetonitrile was then mostly distilled off under reduced pressure and 100 ml of water was added to the residue. The mixture was stirred with 100 ml of methylene chloride. The precipitated solid was filtered off and dried. In this manner 2.60 g of solid were obtained which, according to HPLC analysis, had a purity of 99.3% (a/a), which corresponded to a yield of 15.3% of theory. The methylene chloride phase was separated off, dried and concentrated. This gave 12.72 g of the title compound at a purity of 97.6% (a/a), which corresponded to a yield of 73.4% of theory.

[0194] Melting point: 128° C.

[0195] LC/MS: m/e=339 (MH.sup.+).

[0196] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.36 (s, 3H), 3.87 (q, 2H), 4.03 (s, 2H), 7.33 (m, 2H), 11.98 (s, 1H) ppm.

Example 6: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one

[0197] ##STR00026##

[0198] A mixture of 3.16 g [10 mmol] of 2-chloro-N-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}acetamide and 1.14 g [15 mmol] of ammonium rhodanide in 25 ml of ethanol was heated under reflux for 15 hours. Subsequently, 50 ml of water and 50 ml of methylene chloride were added to the reaction mixture at room temperature. The organic phase was separated off, the aqueous phase extracted again with 50 ml of methylene chloride, the organic phases combined, washed with 50 ml of water, dried over sodium sulfate and concentrated under reduced pressure. This gave 3.33 g of product at a purity of 70.8% (a/a) according to GC/MS analysis (70% of theory).

Example 7: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one (compound A) and 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one (compound B)

[0199] ##STR00027##

[0200] A mixture of 9.81 g [29 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 5.8 g {58 mmol] of 2,2,2-trifluoroethanol and 15 g [116 mmol] of ethyldiisopropylamine (Hünig base) in 200 ml of N,N-dimethylacetamide (DMAC) was stirred at 20° C. for 30 minutes. Then, at 20° C., 9.7 g [95 mmol] of sulfuryl fluoride (SO.sub.2F.sub.2) was introduced and the mixture stirred for 2 hours until the starting material had been virtually completely reacted according to HPLC monitoring. The reaction mixture was concentrated under reduced pressure, the residue taken up in tert-butyl methyl ether (MTBE), extracted twice with water, dried and evaporated. This gave 12.5 g of a thick oil. Analysis by quantitative .sup.19F-NMR showed a content of 77.8% (w/w) of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one (corresponding to a yield of 79.8% of theory) and 12.2% (w/w) of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one (corresponding to a yield of 12.5% of theory). The ratio of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one to 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoro-ethyl)amino]-1,3-thiazol-4(5H)-one was thus 86.4:13.6.

Example 8: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in CH.SUB.2.Cl.SUB.2

[0201] ##STR00028##

[0202] A mixture of 0.98 g [2.9 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 0.58 g {5.8 mmol] of 2,2,2-trifluoroethanol and 1.5 g [11.6 mmol] of ethyldiisopropylamine (Hünig base) in 20 ml of dichloromethane was stirred at 20° C. for 30 minutes. Then, at 20° C., 0.8 g [7.8 mmol] of sulfuryl fluoride (SO.sub.2F.sub.2) was introduced over 4 hours and the mixture further stirred at RT for 12 hours. HPLC monitoring showed that the starting material had been virtually completely reacted. The reaction mixture was concentrated under reduced pressure, the residue taken up in tert-butyl methyl ether (MTBE), extracted twice with water, dried and evaporated. This gave 1.2 g of a thick oil. According to quantitative NMR, the ratio of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one to 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one was 64:27. Yield of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one was 58% and of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one was 22%.

Example 9: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in DMF

[0203] ##STR00029##

[0204] A mixture of log [29.5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 5.9 g {59 mmol] of 2,2,2-trifluoroethanol and 11.4 g [88.4 mmol] of ethyldiisopropylamine (Hünig base) in 150 ml DMF was stirred at 20° C. for 30 minutes. Then, at 20° C., 9 g [88.5 mmol] of sulfuryl fluoride (SO.sub.2F.sub.2) was introduced over 4 hours and the mixture further stirred at RT for 10 hours. The reaction mixture was concentrated under reduced pressure, the residue taken up in tert-butyl methyl ether (MTBE), extracted twice with water, dried and evaporated. This gave 12.4 g of a thick oil. Analysis by quantitative .sup.19F-NMR showed a content of 77% (w/w) of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one (corresponding to a yield of 77.0% of theory) and 13% (w/w) of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one (corresponding to a yield of 13% of theory).

Example 10: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one

[0205] ##STR00030##

[0206] A mixture of 9.81 g [29 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 5.8 g {58 mmol] of 2,2,2-trifluoroethanol and 8.7 g [87 mmol] of K.sub.2CO.sub.3, pot ash, in 200 ml of N,N-dimethylacetamide (DMAC) was stirred at 20° C. for 30 minutes. Then, at 20° C., 9.7 g [95 mmol] of sulfuryl fluoride (SO.sub.2F.sub.2) was introduced and the mixture stirred for 2 hours until the starting material had been virtually completely reacted according to HPLC monitoring. The reaction mixture was concentrated under reduced pressure, water was added and the residue taken up in tert-butyl methyl ether (MTBE), extracted twice with water, dried and evaporated. This gave 12.4 g of a thick oil. Analysis by quantitative .sup.19F-NMR showed a content of 78% (w/w) of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one (corresponding to a yield of 79.4% of theory) and 12% (w/w) of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one (corresponding to a yield of 12.2% of theory).

Example 11: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in toluene

[0207] ##STR00031##

[0208] A mixture of log [29.5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 5.9 g {59 mmol] of 2,2,2-trifluoroethanol and 11.4 g [88.3 mmol] of ethyldiisopropylamine (Hünig base) in 140 ml of toluene was stirred at 20° C. for 30 minutes. Then, at 20° C., 9 g [88.5 mmol] of sulfuryl fluoride (SO.sub.2F.sub.2) were introduced over 6 hours and the mixture stirred at 20° C. for 20 hours. The reaction mixture was washed with water and the toluene concentrated under reduced pressure. The residue of 12.5 g was analyzed by NMR.

[0209] .sup.9F-NMR showed a content of 31% (w/w) of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one (corresponding to a yield of 31.2% of theory) and 58.5% (w/w) of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one (corresponding to a yield of 59% of theory). The ratio of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one to 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one was therefore 34:66.