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

Abstract

The present invention relates to a method for preparing 2-(phenylimino)-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)-1,3-thiazolidin-4-ones of formula (I) ##STR00009## in which Y.sup.1 and Y.sup.2 are independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are 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, wherein an aryl isothiocyanate of formula (VI) ##STR00010## in which Y.sup.1, Y.sup.2, R.sup.1 and R.sup.2 are as defined above, comprising reacting, in the presence of an acetic acid derivative of formula (III) ##STR00011## 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, and in the presence of a base, with an amine of formula (VII) ##STR00012## in which R.sup.3 is as defined above, initially to form the thiourea of formula (II) ##STR00013## in which Y.sup.1, Y.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined above, which is then converted into the compound of formula (I), with the acetic acid derivative of formula (III) being initially present in the reaction mixture prior to the addition to the reaction mixture of at least one of the compounds of formulas (VI) and (VII).

2. 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 the E- and Z-isomers in the mixture.

3. The method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are independently fluorine, chlorine or hydrogen, W is an O(C.sub.1-C.sub.6 alkyl) radical, R.sup.1 and R.sup.2 are independently fluorine, chlorine, C.sub.1-C.sub.3 alkyl or hydrogen and R.sup.3 is optionally substituted phenyl, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 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.

4. The method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are independently fluorine or hydrogen, W is an O(C.sub.1-C.sub.6 alkyl) radical, R.sup.1 and R.sup.2 are independently fluorine, chlorine, hydrogen or methyl and R.sup.3 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.

5. The method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are fluorine, W is an OCH.sub.3 or OC.sub.2H.sub.5 radical, R.sup.1 and R.sup.2 are independently fluorine, hydrogen or methyl and R.sup.3 is C.sub.1-C.sub.6 haloalkyl.

6. The method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are fluorine, W is OCH.sub.3, R.sup.1 is methyl, R.sup.2 is fluorine and R.sup.3 is CH.sub.2CF.sub.3.

7. The method according to claim 1, wherein conversion of the aryl isothiocyanate of formula (VI) into the compound of formula (I) takes place in the presence of a diluent selected from tetrahydrofuran (THF), dioxane, diethyl ether, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), 2-methyl-THF, acetonitrile (ACN), acetone, butyronitrile, ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, methyl isobutyl ketone, ethylene carbonate, propylene carbonate, N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), sulfolane, tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane, toluene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, anisole, n-pentane, n-hexane, n-heptane, n-octane, 1,2,4-trimethylpentane (isooctane), petroleum ether 40/55, special boiling point spirit 80/110, cyclohexane or methylcyclohexane and mixtures thereof.

8. The method according to claim 1, wherein the amine of formula (VII) is present in a molar ratio from 0.95:1 to 2:1 based on the aryl isothiocyanate of formula (VI).

9. The method according to claim 1, wherein the base is an organic base selected from trimethylamine, triethylamine, tributylamine and ethyldiisopropylamine, or that the base is an inorganic base selected from potassium acetate, sodium acetate, lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate and magnesium carbonate.

10. The method according to claim 1, wherein the base is used in a molar ratio from 0.8:1 to 3:1 based on the aryl isothiocyanate of formula (VI).

11. The method according to claim 1, wherein the acetic acid derivative of formula (III) is present in a molar ratio from 0.9:1 to 2:1 based on the aryl isothiocyanate of formula (VI).

12. The method according to claim 7, wherein the diluent is selected from toluene. ortho-xylene, meta-xylene, para-xylene, ethylbenzene, chlorobenzene and a mixture of said diluents and/or the base potassium carbonate.

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

Description

EXAMPLE

Example 1: 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

[0039] A reaction vessel was charged with 10 ml of toluene, 1.216 g [4.32 mmol] of 1-fluoro-2-isothiocyanato-5-methyl-4-[(2,2,2-trifluoroethyl)sulfanyl]benzene, 0.841 g [5.5 mmol] of methyl bromoacetate and 0.967 g [7.5 mmol] of potassium carbonate. 0.743 g [7.5 mmol] of 2,2,2-trifluoroethanamine was added dropwise, with stirring, and stirring at 20-25° C. was then continued for 24 hours. The reaction mixture was a very readily stirrable, thin suspension throughout this time. This was cooled to room temperature, diluted with 10 ml of toluene, and stirred with 15 ml of water, after which the phases were separated, the aqueous phase was extracted with 10 ml of toluene, the combined organic phases were washed with 10 ml of 1 N hydrochloric acid, drying was carried out over sodium sulfate and the organic phase was concentrated. This afforded 1.93 g of product having a purity by HPLC of 90.7%, corresponding to a yield of 96% of theory.

COMPARATIVE EXAMPLES

Comparative Example 1: Synthesis of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}-3-(2,2,2-trifluoroethyl)thiourea in Toluene

[0040] 5.0 g of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline [20.9 mmol, 1.0 equiv.] was added to 30 ml of toluene and to this was added dropwise, at room temperature, 3.2 g of 1,1,1-trifluoro-2-isothiocyanatoethane [23.0 mmol, 1.1 equiv.]. The reaction mixture was stirred at room temperature for 3 hours, resulting in the formation from the original solution of a very thick, poorly stirrable suspension. Monitoring of the reaction indicated only about 85% conversion. The reaction mixture was heated to 50° C. in order to make it partially stirrable again. After 3 hours at 50° C., complete conversion still had not been achieved, consequently the reaction mixture was heated to 70° C. Complete conversion was still not achieved even after 3 hours at 70° C. (HPLC monitoring of the reaction indicated that 0.9% of the aniline was still present). The reaction mixture was cooled to 5° C. and the very thick, pasty suspension transferred to a suction filter as thoroughly as possible and the solid isolated. The solid obtained was washed with cold MTBE and dried under reduced pressure. This afforded 5.1 g of the target product as a beige solid (61% of theory). Concentration of the filtrate gave a further 2.2 g of a brown solid, which had a target product content of approx. 60% (17% of theory). The poor isolated yield is due in part also to the relatively large losses during transfer of the very thick suspension to the suction filter.

Comparative Example 2: Synthesis of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}-3-(2,2,2-trifluoroethyl)thiourea in Methylcyclohexane

[0041] A reaction vessel was charged with 77 ml of methylcyclohexane (MCH) and 11.9 g [50 mmol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline. This was heated to 50° C. and 8.1 g [57.5 mmol] of 1,1,1-trifluoro-2-isothiocyanatoethane was added dropwise at this temperature, with stirring, over a period of approx. 5 minutes. After a few minutes the target product began to precipitate out, causing the reaction mixture to become a thick, unstirrable paste. Even the addition of a further 80 ml of methylcyclohexane did not make the mixture stirrable again. The reaction mixture was cooled to 20° C. and rinsed out of the reaction vessel with large amounts of MCH. The solid was filtered off with suction, washed with MCH and dried. This afforded 18.55 g of product having a purity by HPLC analysis of 98.5% (a/a), corresponding to a yield of 96% of theory. Thus, although the yield is very good, the extremely pasty consistency of the reaction mixture makes the methodology unworkable on an industrial scale.

Comparative Example 3: 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

[0042] 7.1 g of 1,1,1-trifluoro-2-isothiocyanatoethane [95%, 48.0 mmol, 1.2 equiv.] was dissolved in 40 ml of toluene and stirred (400 rpm) with 9.57 g of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline (40.0 mmol, 1.1 equiv.) for 30 min at 20° C., resulting in the formation from the yellowish solution of a suspension containing a white solid. After 1 hour the suspension was no longer stirrable, but monitoring of the reaction by HPLC analyses of the suspension indicated only about 65% conversion. A further 10 ml of toluene was added, the stirring speed was increased to 600 rpm and the reaction mixture was heated to 40° C., as a result of which the mixture became moderately stirrable again. After 3 hours at 40° C. (HPLC monitoring of the reaction showed approx. 87% conversion), 8.3 g of solid potassium carbonate [60.0 mmol, 1.5 equiv.] was added. After a further 30 min, 8.0 g of methyl 2-bromoacetate [52.0 mmol, 1.3 equiv.] was added at 40° C. over a period of 1 hour and the reaction mixture was stirred at 40° C. for 20 hours, resulting in the formation of a suspension of potassium bromide and potassium carbonate in a toluene solution of the target product that was once again readily stirrable. HPLC monitoring of the reaction at this point showed complete conversion of the aniline and only traces of the intermediate thiourea. The reaction mixture was cooled to 20° C., stirred at 20° C. for a further 17 hours and filtered. The solid was washed with a little toluene and the combined filtrates concentrated to 66.8 g of a reddish brown toluene solution, which was shown by HPLC against an external standard to contain 21.10% of the target product (84% of theory) and neither aniline nor the thiourea intermediate.