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

Abstract

The present invention relates to a novel 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. Method for preparing 2-(phenylimino)-3-alkyl-1,3-thiazolidin-4-ones of formula (I) ##STR00029## 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) ##STR00030## 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 defined above and Z is iodine, bromine, chlorine, OSO.sub.2Me, OSO.sub.2Ph, OSO.sub.2(4-Me-Ph), OSO.sub.2CF.sub.3, OSO.sub.2C.sub.2F.sub.5, OSO.sub.2C.sub.3F.sub.7, OSO.sub.2C.sub.4F.sub.9, OSO.sub.2CF.sub.2COOMe, OSO.sub.2CF.sub.2COOEt, OSO.sub.2CF.sub.2COOnPr, OSO.sub.2CF.sub.2COOiPr or OSO.sub.2CF.sub.2COOnBu.

2. The method according to claim 1, wherein the compound of formula (VIII) is obtained from monoarylthioureas of formula (XI) ##STR00031## by reaction with a compound of formula (III) ##STR00032## 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 (XI) is obtained from an aniline of formula (IV) ##STR00033## by reaction with an alkoxycarbonyl isothiocyanate of formula (XII) ##STR00034## in which R.sup.4 is methyl, ethyl or isopropyl, to give an alkyl (phenylcarbamothioyl)carbamate of formula (XIII) ##STR00035## which is then saponified and decarboxylated under acidic or alkaline conditions to give the monoarylthiourea of formula (XI).

4. The method according to claim 1, wherein the compound of formula (VIII) is obtained from 2-halo-N-(phenyl)acetamide of formula (XIV) ##STR00036## in which Hal is chlorine or bromine, by reaction with an alkali metal or ammonium rhodanide of formula (XV)
MSCN  (XV), 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 formula (XIV) is obtained from an aniline of formula (IV) ##STR00037## by reaction with a haloacetyl halide of formula (XVI) ##STR00038## in which 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.2Me, OSO.sub.2Ph, OSO.sub.2(4-Me-Ph), OSO.sub.2CF.sub.3, OSO.sub.2C.sub.2F.sub.5, OSO.sub.2C.sub.3F.sub.7, OSO.sub.2C.sub.4F.sub.9, OSO.sub.2CF.sub.2COOMe, OSO.sub.2CF.sub.2COOEt, OSO.sub.2CF.sub.2COOnPr, OSO.sub.2CF.sub.2COOiPr or OSO.sub.2CF.sub.2COOnBu.

7. The method according to claim 1, wherein Y.sup.1 and Y.sup.2 are 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.2CF.sub.3, OSO.sub.2C.sub.2F.sub.5, OSO.sub.2C.sub.3F.sub.7, OSO.sub.2C.sub.4F.sub.9, OSO.sub.2CF.sub.2COOMe, OSO.sub.2CF.sub.2COOEt, OSO.sub.2CF.sub.2COOnPr, OSO.sub.2CF.sub.2COOiPr or OSO.sub.2CF.sub.2COOnBu.

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.2CF.sub.3, OSO.sub.2C.sub.4F.sub.9, OSO.sub.2CF.sub.2COOMe, OSO.sub.2CF.sub.2COOEt, OSO.sub.2CF.sub.2COOnPr, OSO.sub.2CF.sub.2COOiPr or OSO.sub.2CF.sub.2COOnBu.

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.2CF.sub.3, OSO.sub.2C.sub.4F.sub.9, OSO.sub.2CF.sub.2COOMe, OSO.sub.2CF.sub.2COOiPr.

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, K 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 the formula (I) is in a form of a 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 the formula (I) is carried out in the presence of a solvent selected from acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, hexanol, octanol, isooctanol, cyclopentanol, cyclohexanol, ethylene glycol, glycerol, dimethyl sulfoxide, sulfolane and mixtures thereof.

16. 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).

17. The method according to claim 1, which is carried out in the presence of a base.

18. The method according to claim 17, wherein the base is an organic base 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 and sodium acetate, or that the base is an inorganic base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate and magnesium carbonate.

19. The method according to claim 17, wherein the base is used at a molar ratio from 0.9:1 to 3:1, based on the 2-(phenylimino)-3H-1,3-thiazolidin-4-one of formula (VIII).

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

21. Compound of formula (VIII) ##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.

22. Compound of formula (XI) ##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.

23. Compound of formula (XIII) ##STR00041## 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.

24. The compound according to claim 23, in which R.sup.4 is methyl or ethyl.

25. Compound of formula (XIV) ##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 and Hal is chlorine or bromine.

26. Compound of formula (VIII′) ##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. Compound of formula (X) ##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.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

[0066] ##STR00020##

[0067] 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.

[0068] Melting point: 128° C.

[0069] GC/MS: m/e=315 (M.sup.+, 1 Cl, 33%), 239 (M.sup.+- 76, 43%), 156 (100%).

[0070] .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.

[0071] .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)sulfanyl]phenyl}carbamothioyl)carbamate

[0072] ##STR00021##

[0073] 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.

[0074] 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.

[0075] Melting point: 153-154° C.

[0076] .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.

[0077] .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

[0078] ##STR00022##

[0079] 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.

[0080] 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.

[0081] Melting point: 126° C.

[0082] LC/MS: m/e=371 (MH.sup.+).

[0083] .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

[0084] ##STR00023##

[0085] To a mixture of 893 ml of 1N 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.

[0086] Melting point: 120-122° C.

[0087] LC/MS: m/e=299 (MH.sup.+).

[0088] .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.

[0089] .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

[0090] ##STR00024##

[0091] 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.

[0092] Melting point: 128° C.

[0093] LC/MS: m/e=339 (MH.sup.+).

[0094] .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

[0095] ##STR00025##

[0096] 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)

[0097] ##STR00026##

[0098] A mixture of 138 mg [0.4 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 94.7 mg [0.4 mmol] of 2,2,2-trifluoroethyl trifluoromethylsulfonate and 113 mg [0.82 mmol] of potassium carbonate in 5 ml of acetonitrile was stirred for 18 hours at 20° C. The reaction mixture was filtered, the residue washed with 5 ml of acetonitrile and the filtrate was concentrated. This gave 260 mg of solid. The HPLC analysis showed complete conversion and a ratio of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluorethyl)-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 of 79.9:20.1.

Example 8: Synthesis of 2-[{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}(2,2,2-trifluoroethyl)amino]-1,3-thiazol-4(5H)-one

[0099] ##STR00027##

[0100] A mixture of 1.69 g [5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 2.29 g [6 mmol] of 2,2,2-trifluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate and 1.01 g [10 mmol] of triethylamine in 50 ml of methyl tert-butyl ether (MTBE) was heated to 40° C. for 26 hours and then for 5 hours under reflux. 20 ml of water were then added to the reaction mixture at room temperature. The organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. This gave 3.8 g of a crude product which was purified by column chromatography (eluent cyclohexane/ethyl acetate). This gave 0.73 g of a white solid which, according to HPLC analysis had >99% purity.

[0101] Melting point: 135° C.

[0102] LC/MS: m/e=421 (MH.sup.+).

[0103] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=2.45 (s, 3H), 4.02 (q, 2H), 4.11-4.19 (m, 2H), 4.76 (m, 1H), 4.99 (m, 1H), 7.49 (d, 1H), 7.88 (d, 1H) ppm.

[0104] .sup.19F-NMR (565 MHz, d.sub.6-DMSO): δ=−64.7 (t, 3 F), −68.8 (m, 3F), −122.3 (m, 1F) ppm.

[0105] .sup.13C-NMR (151 MHz, d.sub.6-DMSO): δ=20.3 (Ar—CH.sub.3), 34.7 (SCH.sub.2), 41.9 (SCH.sub.2CO), 52.9 (NCH.sub.2CF.sub.3), 118.8 (C.sub.ArH), 123.8 (NCH.sub.2CF.sub.3), 125.4 (C.sub.ArN), 125.9 (SCH.sub.2CF.sub.3), 130.0 (C.sub.ArS), 132.5 (C.sub.ArH), 144.2 (C.sub.ArMe), 156.8/C.sub.ArF), 187.0 (NCO), 187.1 (N—C(═N)S) ppm.

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 (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)

[0106] ##STR00028##

[0107] A mixture of 169 mg [0.5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 191 mg [0.5 mmol] of 2,2,2-trifluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate and 138 mg [1 mmol] of potassium carbonate in 5 ml of acetonitrile was stirred for 19 hours at 20° C. Analysis by HPLC showed complete conversion and a ratio of products A and B of approximately 80:20.

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 (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)

[0108] A mixture of 169 mg [0.5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 191 mg [0.5 mmol] of 2,2,2-trifluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate and 101 mg [1 mmol] of triethylamine in 5 ml of acetonitrile was stirred for 19 hours at 20° C. Analysis by HPLC showed a conversion of about 82% and a ratio of products A and B of approximately 71:29.

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 (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)

[0109] A mixture of 169 mg [0.5 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 191 mg [0.5 mmol] of 2,2,2-trifluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate and 138 mg [1 mmol] of potassium carbonate in 5 ml of N,N-dimethylacetamide was stirred for 19 hours at 20° C. Analysis by HPLC showed complete conversion and a ratio of products A and B of approximately 90:10.

Example 12: 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)

[0110] The procedure was as in example 11 but 1 mmol of sodium carbonate was used in place of potassium carbonate. Analysis by HPLC showed a conversion of 99% and a ratio of products A and B of approximately 92:8.

Example 13: 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)

[0111] The procedure was as in example 11 but 1 mmol of sodium hydrogencarbonate was used in place of potassium carbonate. Analysis by HPLC shows a conversion of 99% and a ratio of products A and B of approximately 92:8.

Example 14: 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)

[0112] The procedure was as in example 11 but 1 mmol of caesium carbonate was used in place of potassium carbonate. Analysis by HPLC showed a conversion of 100% and a ratio of products A and B of approximately 80:20.

Example 15: 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)

[0113] The procedure was as in example 11 but 1 mmol of triethylamine was used in place of potassium carbonate. Analysis by HPLC shows a conversion of 93% and a ratio of products A and B of approximately 91:9.

Example 16: 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)

[0114] The procedure was as in example 11 but 1 mmol of diisopropylethylamine was used in place of potassium carbonate. Analysis by HPLC showed a conversion of 92% and a ratio of products A and B of approximately 91:9.

Example 17: 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)

[0115] The procedure was as in example 11 but 1 mmol of sodium methoxide (as a 30% solution in methanol) was used in place of potassium carbonate. Analysis by HPLC showed a conversion of 98% and a ratio of products A and B of approximately 95:5.

Example 18: 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)

[0116] The procedure was as in example 11 but the same amount of N-methylpyrrolidone was used in place of N,N-dimethylacetamide. Analysis by HPLC showed a conversion of 100% and a ratio of products A and B of approximately 91:9.

Example 19: 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)

[0117] The procedure was as in example 11 but the same amount of dimethyl sulfoxide was used in place of N,N-dimethylacetamide. Analysis by HPLC showed a conversion of 98% and a ratio of products A and B of approximately 80:20.

Example 20: 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)

[0118] A mixture of 677 mg [2 mmol] of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-1,3-thiazolidin-4-one, 544 mg [2 mmol] of methyl difluoro[(2,2,2-trifluoroethoxy)sulfonyl]acetate and 404 mg [4 mmol] of triethylamine in 20 ml of N,N-dimethylacetamide was stirred at 20° C. for 72 hours. Analysis by HPLC showed a conversion of about 65% and a ratio of products A and B of approximately 91:9.